Genetic risk of Parkinson disease and progression · genetic risk factors, either in the form of...
17
ARTICLE OPEN ACCESS Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts Hirotaka Iwaki, MD, Cornelis Blauwendraat, PhD, Hampton L. Leonard, MS, Ganqiang Liu, PhD, Jodi Maple-Grødem, PhD, Jean-Christophe Corvol, MD, PhD, Lasse Pihlstrøm, MD, PhD, Marlies van Nimwegen, PhD, Samantha J. Hutten, PhD, Khanh-Dung H. Nguyen, PhD, Jacqueline Rick, PhD, Shirley Eberly, MS, Faraz Faghri, MS, Peggy Auinger, MS, Kirsten M. Scott, MRCP, MPhil, Ruwani Wijeyekoon, MRCP, Vivianna M. Van Deerlin, MD, PhD, Dena G. Hernandez, PhD, Aaron G. Day-Williams, PhD, Alexis Brice, MD, Guido Alves, MD, PhD, Alastair J. Noyce, MRCP, PhD, Ole-Bjørn Tysnes, MD, PhD, Jonathan R. Evans, MRCP, PhD, David P. Breen, MRCP, PhD, Karol Estrada, PhD, Claire E. Wegel, MPH, Fabrice Danjou, MD, PhD, David K. Simon, MD, PhD, Bernard Ravina, MD, Mathias Toft, MD, PhD, Peter Heutink, PhD, Bastiaan R. Bloem, MD, PhD, Daniel Weintraub, MD, Roger A. Barker, MRCP, PhD, Caroline H. Williams-Gray, MRCP, PhD, Bart P. van de Warrenburg, MD, PhD, Jacobus J. Van Hilten, MD, PhD, Clemens R. Scherzer, MD, Andrew B. Singleton, PhD, and Mike A. Nalls, PhD Neurol Genet 2019;5:e348. doi:10.1212/NXG.0000000000000348 Correspondence Dr. Nalls [email protected] Abstract Objective To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. Methods We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. Results We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]). Conclusions This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials. From the Laboratory of Neurogenetics (H.I., C.B., H.L.L., F.F., D.G.H., A.B.S., M.A.N.), National Institute on Aging, National Institutes of Health, Bethesda; Data Tecnica International (H.I., M.A.N.), Glen Echo, MD; Precision Neurology Program (G.L., C.R.S.), Harvard Medical School, Brigham and Women’s Hospital; Neurogenomics Laboratory (G.L., C.R.S.), Harvard Medical School, Brigham and Women’s Hospital; Ann Romney Center for Neurologic Diseases (G.L., C.R.S.), Brigham and Women’s Hospital, Boston, MA; The Norwegian Centre for Movement Disorders (J.M.-G., G.A.), Stavanger University Hospital; Department of Chemistry (J.M.-G., G.A.), Bioscience and Environmental Engineering, University of Stavanger, Norway; Assistance-Publique Hˆ opitaux de Paris (J.-C.C.), ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Piti´ e-Salpˆ etri` ere Hospital, Paris, France; Department of Neurology (L.P., M.T.), Oslo University Hospital, Norway; Department of Neurology (M.N., B.R.B., B.P.W.), Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands; Michael J Fox Foundation (S.J.H.), New York; Translational Genome Sciences (K.-D.H.N, K.E.), Biogen, Cambridge, MA; Department of Neurology University of Pennsylvania (J.R.), Philadelphia, PA; Department of Biostatistics and Computational Biology (S.E.), University of Rochester, NY; Department of Computer Science (F.F.), University of Illinois Urbana-Champaign; Department of Neurology (P.A.), Center for Health + Technology, University of Rochester, NY; Department of Clinical Neurosciences (K.M.S., R.W.), University of Cambridge, John van Geest Centre for Brain Repair, UK; Department of Pathology and Laboratory Medicine (V.M.V.D.), Center for Neurodegenerative Disease Research, Parelman School of Medicine at the University of Pennsylvania, Philadelphia; Genetics and Pharmacogenomics (A.G.D.-W.), Merck Research Laboratory, Boston, MA; Statistical Genetics (A.G.D.-W.), Biogen, Cambridge, MA; Institut du cerveau et de la moelle ´ epini` ere ICM (A.B., F.D.); Sorbonne Universit´ e SU (A.B.); INSERM UMR 1127 (A.B.), Paris, France; Department of Neurology (G.A.), Stavanger University Hospital, Norway; Preventive Neurology Unit (A.J.N.), Wolfson Institute of Preventive Medicine, Queen Mary University of London; Department of Molecular Neuroscience (A.J.N.), UCL Institute of Neurology, London, UK; Department of Neurology (O.-B.T.), Haukeland University Hospital; University of Bergen (O.-B.T.), Bergen, Norway; Department of Neurology (J.R.E.), Nottingham University NHS Trust, UK; Centre for Clinical Brain Sciences (D.P.B.), University of Edinburgh; Anne Rowling Regenerative Neurology Clinic (D.P.B.), University of Edinburgh; Usher Institute of Population Health Sciences and Informatics (D.P.B.), University of Edinburgh, Scotland; Department of Medical and Molecular Genetics (C.E.W.), Indiana University, Indianapolis; Department of Neurology (D.K.S.), Beth Israel Deaconess Medical Center; Harvard Medical School (D.K.S.), Boston; Voyager Therapeutics (B.R.), Cambridge, MA; Department of Neurology (B.R.), University of Rochester School of Medicine, NY; Institute of Clinical Medicine (M.T.), University of Oslo, Norway; German Center for Neurodegenerative Diseases-Tubingen (P.H.); HIH Tuebingen (P.H.), Germany; Department of Psychiatry (D.W.), University of Pennsylvania School of Medicine; Department of Veterans Affairs (D.W.), Philadelphia, PA; and Department of Clinical Neurosciences (R.A.B., C.H.W.-G.), University of Cambridge, UK; Department of Neurology (J.J.V.H.), Leiden University Medical Center, The Netherlands. Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the NIH. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1
Transcript of Genetic risk of Parkinson disease and progression · genetic risk factors, either in the form of...
ARTICLE OPEN ACCESS
Genetic risk of Parkinson disease andprogressionAn analysis of 13 longitudinal cohorts
Hirotaka Iwaki MD Cornelis Blauwendraat PhD Hampton L Leonard MS Ganqiang Liu PhD
Jodi Maple-Groslashdem PhD Jean-Christophe Corvol MD PhD Lasse Pihlstroslashm MD PhD
Marlies van Nimwegen PhD Samantha J Hutten PhD Khanh-Dung H Nguyen PhD Jacqueline Rick PhD
Shirley Eberly MS Faraz Faghri MS Peggy Auinger MS Kirsten M Scott MRCP MPhil
Ruwani Wijeyekoon MRCP Vivianna M Van Deerlin MD PhD Dena G Hernandez PhD
Aaron G Day-Williams PhD Alexis Brice MD Guido Alves MD PhD Alastair J Noyce MRCP PhD
Ole-Bjoslashrn Tysnes MD PhD Jonathan R Evans MRCP PhD David P Breen MRCP PhD Karol Estrada PhD
Claire E Wegel MPH Fabrice Danjou MD PhD David K Simon MD PhD Bernard Ravina MD
Mathias Toft MD PhD Peter Heutink PhD Bastiaan R Bloem MD PhD Daniel Weintraub MD
Roger A Barker MRCP PhD Caroline H Williams-Gray MRCP PhD Bart P van de Warrenburg MD PhD
Jacobus J Van Hilten MD PhD Clemens R Scherzer MD Andrew B Singleton PhD and Mike A Nalls PhD
Neurol Genet 20195e348 doi101212NXG0000000000000348
Correspondence
Dr Nalls
nallsmmailnihgov
AbstractObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variablesmeasuring disease progression
MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression A total of 23423 visits by4307 patients of European ancestry from 13 longitudinal cohorts in Europe North America and Australia were analyzed
ResultsWe confirmed the importance of GBA on phenotypes GBA variants were associated with the development of daytimesleepiness (pN370S hazard ratio [HR] 328 [169ndash634]) and possible REM sleep behavior (pT408M odds ratio 648[204ndash2060]) We also replicated previously reported associations ofGBA variants with motorcognitive declines The othergenotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom(Hoehn and Yahr scale 30 HR 133 [116ndash152] for the C allele of rs76904798) and an intronic variant in PMVK and thedevelopment of wearing-off effects (HR 166 [119ndash231] for the C allele of rs114138760) Age at onset was associated withTMEM175 variant pM393T (minus072 [minus121 to minus023] in years) the C allele of rs199347 (intronic region of GPNMB 070[027ndash114]) and G allele of rs1106180 (intronic region of CCDC62 062 [021ndash103])
ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk in particular GBA variants also contribute tothe heterogeneity of multiple motor and nonmotor aspects Accounting for genetic variability will be a useful factor inunderstanding disease course and in minimizing heterogeneity in clinical trials
From the Laboratory of Neurogenetics (HI CB HLL FF DGH ABS MAN) National Institute on Aging National Institutes of Health Bethesda Data Tecnica International(HI MAN) Glen Echo MD Precision Neurology Program (GL CRS) Harvard Medical School Brigham and Womenrsquos Hospital Neurogenomics Laboratory (GL CRS) HarvardMedical School Brigham and Womenrsquos Hospital Ann Romney Center for Neurologic Diseases (GL CRS) Brigham and Womenrsquos Hospital Boston MA The Norwegian Centre forMovement Disorders (JM-G GA) Stavanger University Hospital Department of Chemistry (JM-G GA) Bioscience and Environmental Engineering University of StavangerNorway Assistance-Publique Hopitaux de Paris (J-CC) ICM INSERM UMRS 1127 CNRS 7225 ICM Department of Neurology and CIC Neurosciences Pitie-Salpetriere Hospital ParisFrance Department of Neurology (LP MT) Oslo University Hospital Norway Department of Neurology (MN BRB BPW) Donders Institute for Brain Cognition and BehaviourRadboud University Medical Centre Nijmegen The Netherlands Michael J Fox Foundation (SJH) New York Translational Genome Sciences (K-DHN KE) Biogen Cambridge MADepartment of Neurology University of Pennsylvania (JR) Philadelphia PA Department of Biostatistics and Computational Biology (SE) University of Rochester NY Department ofComputer Science (FF) University of Illinois Urbana-Champaign Department of Neurology (PA) Center for Health + Technology University of Rochester NY Department of ClinicalNeurosciences (KMS RW) University of Cambridge John van Geest Centre for Brain Repair UK Department of Pathology and Laboratory Medicine (VMVD) Center forNeurodegenerative Disease Research Parelman School of Medicine at the University of Pennsylvania Philadelphia Genetics and Pharmacogenomics (AGD-W) Merck ResearchLaboratory Boston MA Statistical Genetics (AGD-W) Biogen Cambridge MA Institut du cerveau et de la moelle epiniere ICM (AB FD) Sorbonne Universite SU (AB) INSERMUMR1127 (AB) Paris France Department of Neurology (GA) Stavanger University Hospital Norway Preventive Neurology Unit (AJN) Wolfson Institute of Preventive MedicineQueen Mary University of London Department of Molecular Neuroscience (AJN) UCL Institute of Neurology London UK Department of Neurology (O-BT) Haukeland UniversityHospital University of Bergen (O-BT) Bergen Norway Department of Neurology (JRE) Nottingham University NHS Trust UK Centre for Clinical Brain Sciences (DPB) Universityof Edinburgh Anne Rowling Regenerative Neurology Clinic (DPB) University of Edinburgh Usher Institute of Population Health Sciences and Informatics (DPB) University ofEdinburgh Scotland Department of Medical and Molecular Genetics (CEW) Indiana University Indianapolis Department of Neurology (DKS) Beth Israel Deaconess MedicalCenter HarvardMedical School (DKS) Boston Voyager Therapeutics (BR) CambridgeMA Department of Neurology (BR) University of Rochester School ofMedicine NY Instituteof Clinical Medicine (MT) University of Oslo Norway German Center for Neurodegenerative Diseases-Tubingen (PH) HIH Tuebingen (PH) Germany Department of Psychiatry(DW) University of Pennsylvania School of Medicine Department of Veterans Affairs (DW) Philadelphia PA andDepartment of Clinical Neurosciences (RAB CHW-G) Universityof Cambridge UK Department of Neurology (JJVH) Leiden University Medical Center The Netherlands
Go to NeurologyorgNG for full disclosures Funding information is provided at the end of the article
The Article Processing Charge was funded by the NIH
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal
Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1
Parkinson disease is one of the most common neurodegen-erative diseases with an estimated lifetime risk as high as1ndash21 Parkinson disease is traditionally characterized bymotor features such as bradykinesia rigidity and tremorHowever in addition to these motor symptoms patients withParkinson disease also develop nonmotor symptoms(NMSs) which include depression cognitive decline sleepabnormalities reduced olfaction and autonomic dysfunc-tion2 Collectively the combined spectrum of motor andNMSs more accurately reflects the multisystem nature of thedisease Patients with Parkinson disease may present withvarious combinations of symptoms and show differences inthe rates of progression3 The application of modern molec-ular genetic approaches over the last decade has revealeda significant number of genetic risk loci for idiopathic Par-kinson disease4ndash7 However in comparison with case-controlgenome-wide association study (GWAS) analyzing how ge-netic factors influence clinical presentation and progressionrequires longitudinal cohorts with much more detailedobservations Such data are sparse and individual cohorts areoften small in size and quite varied posing a challenge both insample size and heterogeneity
In an attempt to address these issues we collected data from13 distinct longitudinal Parkinson disease cohorts with de-tailed clinical data including assessment of disease pro-gression We sought to determine whether Parkinson diseasegenetic risk factors either in the form of known GWAS var-iants or an aggregate genetic risk score (GRS) are associatedwith changes in clinical progression and the disease features
MethodsStudy design and participantsA total of 13 Parkinson disease cohorts from North AmericaEurope and Australia participated in the study Nine wereprospective observational cohorts and the rest were fromrandomized clinical trials The observational cohorts wereDrug Interaction with Genes in Parkinsonrsquos Disease(DIGPD) Harvard Biomarkers Study (HBS) Oslo Parkin-sonrsquos Disease study (partly including retrospective data) TheNorwegian ParkWest study (ParkWest) Parkinsonrsquos DiseaseBiomarker Program (PDBP) Parkinsonism Incidence andCognitive and Non-motor heterogeneity In CambridgeShire(PICNICS) Parkinsonrsquos Progression Markers Initiative
(PPMI) Profiling Parkinsonrsquos disease study (ProPark) andthe Morris K Udall Centers for Parkinsonrsquos Research (Udall)The 4 cohorts from randomized clinical trials were Deprenyland Tocopherol Antioxidative Therapy of Parkinsonism(DATATOP) NIH Exploratory Trials in Parkinsonrsquos DiseaseLarge Simple Study 1 ParkFit study (ParkFit) and ParkinsonResearch Examination of CEP-1347 Trial with a subsequentprospective study (PreCEPTPostCEPT) Information onthese cohorts can be found in appendix e-1 (linkslwwcomNXGA169) Subsets of participants from the cohorts whoprovided DNA and were nonrelated participants with PDdiagnosed at age 18 years or later and of European ancestrywere included in the study Participantsrsquo information andgenetic samples were obtained under appropriate writtenconsent and with local institutional and ethical approvals
Genotyping SNPs and calculation of GRSOslo samples were genotyped on the Illumina InfiniumOmniExpress array DIGPD samples were genotyped byIllumina Multi-Ethnic Genotyping Array and all other sam-ples were genotyped on the NeuroX array8 The qualitycontrol process of variant calling included GenTrain scorelt07 minor allele frequency (MAF) gt005 (for sample qualitycontrol but not in our analysis of rare risk factors) and Hardy-Weinberg equilibrium test statistic gt10minus6 Sample-specificquality control included a sample call rate of gt095 confir-mation of sex through genotyping homozygosity quantifiedby F within plusmn 3 SD from the population mean Europeanancestry confirmed by principal-components analysis with1000 Genomes data as the reference and genetic relatednessof any 2 individuals lt0125 Detailed information regardingNeuroX and the quality control process has been describedpreviously9 In the present study we investigated 31 singlenucleotide polymorphisms (SNPs) previously shown to besignificantly associated with Parkinson disease10ndash12 In addi-tion we also calculated a GRS for each participant based onthese variants The scores were transformed into Z-scoreswithin each cohort and treated as an exposure with effectestimates based on 1 SD change from the population meanThe list of 31 SNPs and the GRS calculation method areprovided in table e-1 (linkslwwcomNXGA170)
Furthermore principal components (PCs) were created foreach data set from genotypes using PLINK For the PC calcu-lation variants were filtered for MAF (gt005) genotype miss-ingness (lt005) and Hardy-Weinberg equilibrium (p ge 10minus5)
GlossaryESS = Epworth Sleepiness Scale FDR = false discovery rate GRS = genetic risk score GWAS = genome-wide associationstudy HR = hazard ratio HY = Hoehn and Yahr scale MAF = minor allele frequency MDS = Movement Disorder SocietyMMSE = Mini-Mental State Examination MoCA = Montreal Cognitive Assessment MSQ = Mayo Sleep QuestionnaireNMS = nonmotor symptom OR = odds ratio PC = principal component PDSS = Parkinsonrsquos Disease Sleep Scale PPMI =Parkinsonrsquos Progression Markers Initiative RBD = rapid eye movement sleep behavior disorder RBDSQ = RBD ScreeningQuestionnaireRLS = restless legs syndrome SEADL = Schwab and England Activities of Daily Living ScaleUPDRS =UnifiedParkinsonrsquos Disease Rating Scale
2 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
The remaining variants were pruned (using a 50-kb windowwith a 5 SNP shift per window and r2 threshold of 05) and PCswere calculated using the pruned variants
MeasurementsThe following clinicalmeasurements and binomial outcomeswererecorded longitudinally (table e-2 linkslwwcomNXGA171)total and subscores of the Unified Parkinsonrsquos Disease RatingScale (UPDRS) or the Movement Disorder Society revisedUPDRS version (MDS-UPDRS) modified Hoehn and Yahrscales (HY) modified Schwab and England Activities of DailyLiving Scale and scores for the Mini-Mental State Examination(MMSE) The SCales for Outcomes in PArkinsons disease(SCOPA)-Cognition and Montreal Cognitive Assessment(MoCA) Each was treated as a continuous outcome For theUPDRS and MDS-UPDRS scores specifically we took Z-scoresof the total and subscores (except for part 4 at baseline) tocompare the original and revised UPDRS versions The conver-sionwas applied to the scores for all subsequent visits ForUPDRSpart 4most participants had very low scores or 0 at baseline sowenormalized across all observations within each cohort We alsoanalyzed binomial outcomes If we had access to the raw data weused common cutoff values which had been tested and reportedspecificity of 85 or more in patientsrsquo population The binomialoutcomes include existence of family history (1st-degree relative1st- and 2nd-degree relatives in HBS PreCEPT ProPark andUdall) hyposmia (University of Pennsylvania Smell IdentificationTest lt 2113 or answering ldquoyesrdquo to question 2 in the NMS ques-tionnaire) cognitive impairment (SCOPA-Cognition lt 23MMSE lt 27 or MoCA lt 241415 or diagnosed with TheDiagnostic and StatisticalManual ofMental Disorders -IV criteria fordementia) wearing off (UPDRSMDS-UPDRSpart 4 off timegt0or physicianrsquos diagnosis) dyskinesia (UPDRSMDS-UPDRS part4 dyskinesia time gt0 or physicianrsquos diagnosis) depression (BeckDepression Inventory gt 14 [PICNICS used 9 instead of 14]HamiltonDepression Rating Scale gt9 Geriatric Depression Scale[GRS] gt 516 or physicianrsquos diagnosis) constipation (MDS-UPDRS part 1 item 11 gt 0 or answering ldquoyesrdquo to question 5 inthe NMS questionnaire) excessive daytime sleepiness (Epworthsleepiness scale gt 917 insomnia [MDS-UPDRS part 1 item 7 gt0] rapid eye movement sleep behavior disorder [RBD]) (an-swered ldquoyesrdquo to question 1 on the Mayo Sleep Questionnaire[MSQ]18 or RBD screening questionnaire [RBDSQ gt5]19
restless legs syndrome [RLS]) (answered ldquoyesrdquo to MSQ ques-tion 320 or RLS diagnosis positive by RBDSQ) and the pro-gression to HY ge 3 (HY3 representing moderate to severedisease) The individual definitions of these binomial outcomesare summarized in table e-2 (linkslwwcomNXGA171) Agesex years of education age at motor symptom onset andwhether the patient was treated with levodopa or dopamineagonists at each visit were also recorded for adjustments
Statistical analysis
Cohort-level analysisWe analyzed the association between exposures and out-comes using appropriate additive models Covariates of in-terest were not available for all cohorts therefore the model
specifications were slightly different between cohorts (de-tailed in table e-3 linkslwwcomNXGA172) Briefly theassociations between an SNPGRS and age at onset wereanalyzed by linear regression modeling adjusting for pop-ulation stratification (PC1 and PC2) The association be-tween family history of Parkinson disease and SNPGRS wasanalyzed with a logistic regression model adjusting for PC12For continuous variables linear regressionmodeling adjustingfor sex education PC12 age at onset years from diagnosisfamily history and treatment status was applied For thosewho had multiple observations random intercept was addedto adjust for repeated measurements of the same individualFor binomial outcomes the logistic regression at baselineobservation was applied using the same covariates as thecontinuous models Those that were negative at baseline werefurther analyzed by a Cox regression with the same covariatesbut with treatment status as a time-varying covariate Obser-vations with missing variables were excluded from the analyses
Meta-analysisWe applied inverse weighting (precision method) for eachcombination of outcome-predictor association and combinedthe estimates from the 13 different cohorts in a fixed effectmodel Multiple test correction for SNPs was controlled withan overall false discovery rate (FDR) of 005 per outcomebeing considered significant Similarly multiple testing ofoutcomes for GRS was corrected with an FDR of 005 butacross all traits In addition as a test of homogeneity I2 indicesand forest plots were used for quantitative assessment Asa sensitivity analysis we conducted up to 13 iterations of themeta-analyses for the 12 cohorts excluding each cohort periteration This analysis provides information regarding het-erogeneity of the cohorts and how one specific cohort ex-clusion affects the results The range of estimates andmaximum p values for the iterations were included Finally weconducted the 13-cohort meta-analysis in a random effectsmodel with restricted maximum likelihood estimation usingthe same multiple testing correction
All the above analyses were conducted with PLINK version 19and R version 344 (64-bit) Statistical tests were all 2 sided
Data availabilityQualified investigators can request raw data through theorganizationsrsquo homepages (PDBP pdbpnindsnihgovPPMI ppmi-infoorg) or collaboration
ResultsA total of 23423 visits by 4307 patients with a median follow-up period of 297 years (quartile range of [163ndash494] years)were eligible for the analysis The baseline characteristics ofthe cohorts are shown in table 1 The mean ages at onsetvaried from 54 to 69 years the average disease durations atcohort entry ranged from less than 1 to 10 years and themeanobservation periods were between 12 and 68 years AllDATATOP ParkWest PPMI and PreCEPT participants
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 3
Table 1 Summary characteristics of 13 cohorts
DATATOP DIGPD HBSNET-PDLS1 Oslo ParkFit ParkWest PDBP PICNICS PPMI
PreCEPTPostCEPT ProPark Udall
Cohort size n 440 311 580 406 317 335 150 422 120 357 321 296 252
Follow-upduration y
122 (041) 219 (151) 153 (087) 448 (145) 464 (310) 197 (000) 304 (009) 206 (170) 304 (163) 487 (135) 679 (095) 462 (114) 377 (181)
Female n () 146 (332) 121 (389) 201 (347) 148 (365) 107 (338) 110 (328) 57 (380) 174 (412) 43 (358) 121 (339) 106 (330) 105 (355) 73 (290)
Family historyn ()
86 (209) 69 (223) 148 (255) 59 (145) 43 (140) mdash 17 (113) 54 (128) 19 (158) 48 (135) 93 (292) 76 (259) 71 (284)
Age at onset y 5865 (917) 5941 (980) 6216 (1046) 6064 (945) 5433 (1006) 6079 (865) 6727 (926) 5851 (1028) 6894 (934) 6145 (955) 5947 (922) 5314 (1060) 6426 (864)
Baseline fromdiagnosis y
114 (117) 260 (157) 409 (463) 150 (100) 1013 (604) 518 (444) 013 (012) 568 (564) 023 (048) 054 (054) 080 (083) 656 (467) 621 (538)
Levodopa usen ()
0 (00) 198 (639) 415 (716) 207 (512) mdash mdash 0 (00) 255 (604) 36 (300) 0 (00) 0 (00) 202 (682) 215 (853)
Dopamineagonist use n ()
0 (00) 228 (733) 224 (386) 280 (693) mdash mdash 0 (00) 61 (145) 22 (183) 0 (00) 1 (03) 222 (750) 118 (468)
Modified HY 161 (053) 175 (055) 214 (064) mdash 219 (064) 208 (033) 186 (058) 204 (069) 164 (067) 155 (050) 175 (048) 251 (079) 229 (068)
UPDRS1 mdash 769 (450) 170 (159) 131 (145) mdash mdash 195 (176) 990 (611) mdash 540 (397) 084 (119) mdash 192 (199)
UPDRS2 mdash 772 (466) 921 (523) 729 (386) mdash mdash 819 (422) 1114 (801) mdash 580 (411) 611 (320) mdash 1074 (713)
UPDRS3 mdash 2037 (1023) 1930 (958) 1777 (832) 1542 (1030) mdash 2209 (977) 2364 (1308) mdash 2088 (900) 1869 (765) mdash 2292 (1109)
UPDRS4 mdash 066 (256) 225 (205) 134 (149) mdash mdash 057 (114) 220 (317) mdash mdash mdash mdash 202 (275)
MDS_UPDRS total mdash 3643 (1602) mdash mdash mdash mdash mdash 4688 (2404) 4727 (1797) mdash mdash mdash mdash
UPDRS total 2468 (1156) mdash 3233 (1428) 2767 (1162) mdash 3211 (1010) 3279 (1391) mdash mdash mdash 2539 (1010) mdash 3264 (1828)
MMSE 2899 (135) 2838 (173) 2835 (217) mdash mdash 2809 (161) 2788 (227) mdash 2871 (143) mdash 2929 (107) 2705 (250) 2683 (350)
MoCA mdash mdash mdash mdash mdash mdash mdash 2544 (340) mdash 2717 (223) mdash mdash 2437 (363)
SEADL 9155 (649) 8055 (2902) mdash 9159 (606) mdash mdash 8940 (735) 8511 (1310) mdash 9318 (591) 9277 (526) mdash 8053 (1756)
Hyposmia n () mdash 89 (289) mdash mdash mdash mdash 54 (360) 276 (654) mdash 164 (459) mdash 173 (638) 69 (670)
Cognitiveimpairment n ()
26 (59) 3 (10) 74 (130) 29 (71) mdash 55 (164) 27 (180) 96 (227) 11 (92) 28 (78) 3 (09) 77 (270) 29 (115)
Motorfluctuation n ()
mdash 40 (129) 228 (399) 103 (254) mdash mdash 4 (27) 129 (481) 1 (08) mdash mdash 94 (324) 75 (354)
Dyskinesia n () 4 (09) 13 (42) 207 (362) 5 (12) mdash mdash 2 (13) 196 (464) 0 (00) mdash mdash 81 (276) 44 (228)
Continued
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were dopaminergic therapy naive at baseline patients in theother cohorts were not In the primary analysis of 13 cohorts17 associations were identified as significant after FDR cor-rection (table 2 and more information in table e-4 linkslwwcomNXGA173) Overwhelmingly 10 were associated withGBA variants In particular GBA pE365K (rs2230288) wasassociated with 237- (153ndash366) (95 CI) fold higher oddsof having cognitive impairment at baseline (p = 109 times 10minus4)and 278- (188ndash411) fold higher hazard ratio (HR) of de-veloping cognitive impairment during follow-up among thosewho were negative for cognitive impairment at baseline (p =297 times 10minus7) This SNPwas also associated with a higher meanon the HY at 010 (004ndash016) (p = 153 times 10minus3) but the testof homogeneity was rejected (p= 0017 I2 = 489) In additionit was associated with the development of an RBD among thosewho did not have the disorder at baseline OtherGBAmutationspN370S (rs767763715) and pT408M (rs75548401) wereboth associated with a higher HR of reaching HY3 (459[260ndash810] for pN370S [p = 158 times 10minus7] and 193 [134ndash278]for pT408M [p = 440 times 10minus4]) GBA pN370N was also as-sociated with a higher risk of developing wearing-off dyskinesiaand daytime sleepiness pT408M was associated with a 648(204ndash2060) times higher odds ratio (OR) of having an RBDsymptom at baseline (p = 153 times 10minus3)
Two LRRK2 variants in our 31 SNPs of interest were signifi-cantly associated with outcomes LRRK2 pG2019S(rs34637584) was associated with higher odds of having a familyhistory of Parkinson disease (OR 354 [172ndash729] p = 606 times10minus4) and the T allele of rs76904798 (intergenic at the 59 end ofLRRK2) was associated with a higher HR of reaching HY3 (HR133 [116ndash152] for the T allele p = 527 times 10minus5)
Age at onset was inversely associated with theZ value of the GRS(minus060 [minus089 to minus031] years per +1 SD p = 533 times 10minus5)Moreover it was associated with rs34311866 (TMEM175pM393T) theC allele of rs199347 (intronic region ofGPNMB)and the G allele of rs1106180 (intronic region of CCDC62)
The majority (1417) of associations showed good accordacross cohorts (I2 lt 50) and the forest plots (figures 1ndash3) alsoillustrate this qualitatively Furthermore up to 13 iterations of theleave-one-out analysis assessed 15 associations of which out-comes were measured in more than 2 cohorts and showeda small range of betas Themaximum p value of 13 iterations wasless than 005 for all associations except for rs114138769 (intronof PMVK) and rs76763715 (GBA pN370S) for wearing-off Ameta-analysis with a random effect model also detected 9 asso-ciations after the same FDR correction although the model ismore conservative than a fixed model
DiscussionWe conducted a meta-analysis with 13 longitudinal patientcohorts and identified multiple associations between geno-types and clinical phenotypic characteristics includingTa
ble
1Su
mmarych
arac
teristicsof13
cohorts(con
tinue
d)
DATA
TOP
DIG
PD
HBS
NET
-PD
LS1
Oslo
Park
Fit
Park
West
PDBP
PICNICS
PPMI
Pre
CEP
TPostCEP
TPro
Park
Udall
Depre
ssionn
()
12(27)
97(316)
35(109)
40(99)
mdashmdash
20(133)
49(116)
27(225)
113(317)
73(227)
48(163)
63(250)
RLS
n(
)mdash
44(145)
37(109)
mdashmdash
mdashmdash
91(233)
mdash23
(64)
mdashmdash
mdash
Con
stipationn
()
9(20)
62(203)
mdashmdash
mdashmdash
17(113)
239(566)
29(242)
113(317)
mdash13
8(466)
mdash
RBDn
()
mdashmdash
mdashmdash
mdashmdash
mdash19
7(505)
mdash93
(261)
mdashmdash
mdash
Daytim
esleepinessn
()
5(11)
138(448)
mdashmdash
mdashmdash
25(167)
165(391)
25(208)
55(154)
mdash12
6(426)
mdash
Inso
mnian
()
11(25)
107(351)
202(351)
mdashmdash
mdash45
(300)
295(699)
62(517)
78(218)
mdash83
(280)
mdash
HYge30
n(
)0(00)
4(13)
71(124)
12(30)
22(145)
17(51)
11(73)
71(168)
13(108)
1(03)
0(00)
117(408)
57(230)
AbbreviationsDATA
TOP=Dep
renyl
andTo
copher
olA
ntioxidativeTh
erap
yofParkinso
nismD
IGPD=Dru
gInteractionwithGen
esin
Par
kinso
nrsquosDisea
seH
BS=Har
vard
Biomarke
rsStudy
HY=Hoeh
nan
dYa
hrscale
MDS=Move
men
tDisord
erSo
cietyMMSE
=Mini-Men
talS
tate
ExaminationM
oCA=Montrea
lCogn
itiveAsses
smentNET-PDLS
=NIH
Exploratory
Trialsin
Parkinso
nrsquosDisea
seLa
rgeSimple
Study1
Oslo=OsloPDstudy
ParkFit=ParkFitstudy
ParkWes
t=theNorw
egianParkWes
tstudy
PDBP=Par
kinso
nrsquosDisea
seBiomarker
Pro
gram
PICNICS=Parkinso
nismInciden
cean
dCogn
itivean
dNon-m
otorhetero
geneity
InCam
bridge
Shire
PPMI=
Parkinso
nrsquosPro
gres
sionMarke
rsInitiative
Pro
Park=Pro
filin
gParkinso
nrsquosDisea
sestudy
RBD=REM
slee
pbeh
aviordisord
erR
LS=restless
legs
syndro
me
SEADL=Sc
hwab
andEn
glan
dActivitiesofDaily
Living
Scale
UPDRS=UnifiedParkinso
nrsquosDisea
seRatingSc
ale
Continuousva
riab
lesweresu
mmarized
asmea
n(SD)
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 5
Table 2 Meta-analysis for 13 cohorts and the results of sensitivity analysis
Outcome rsNo
Known geneor nearestgene
No ofcohorts
Scale of theeffect
Fixed effect model
Test ofhomogeneity I2 ()
Leave-one-out analysis Random effect model
Estimate (95 CI) pEstimate (Min toMax) Max p Estimate (95 CI) p
Wearing-off rs114138760 intron_PMVK 9 Multiplicative (HR) 166 (119 to 231) 262E-03 0322 1258 166 (144 to 181) 622E-02 165 (114 to 238) 739E-03
Dyskinesia rs76763715 GBAN370S 8 Multiplicative (HR) 301 (181 to 501) 217E-05 0011 6053 300 (198 to 405) 226E-02 249 (106 to 586) 373E-02
HY ge 30 rs76763715 GBAN370S 6 Multiplicative (HR) 459 (260 to 810) 158E-07 0654 000 459 (402 to 541) 200E-05 459 (260 to 810) 158E-07a
Wearing-off rs76763715 GBAN370S 6 Multiplicative (HR) 203 (128 to 321) 256E-03 0021 6270 202 (161 to 265) 867E-02 192 (085 to 433) 114E-01
Daytimesleepiness
rs76763715 GBAN370S 6 Multiplicative (HR) 328 (169 to 634) 424E-04 0467 000 330 (285 to 438) 375E-03 328 (169 to 634) 424E-04a
HY ge 30 rs75548401 GBAT408M 8 Multiplicative (HR) 193 (134 to 278) 440E-04 0208 3243 193 (170 to 241) 108E-02 196 (122 to 314) 522E-03
pRBD (baseline) rs75548401 GBAT408M 2 Multiplicative (OR) 648 (204 to 2060) 153E-03 0118 5906 mdash mdash 625 (102 to 3820) 472E-02
HY rs2230288 GBAE365K 12 Continuous 010 (004 to 016) 153E-03 0017 4890 010 (008 to 011) 102E-02 011 (002 to 021) 188E-02
Cognitiveimpairment(baseline)
rs2230288 GBAE365K 8 Multiplicative (OR) 237 (153 to 366) 109E-04 0794 000 237 (220 to 259) 857E-04 237 (153 to 366) 109E-04a
Cognitiveimpairment
rs2230288 GBAE365K 9 Multiplicative (HR) 278 (188 to 411) 297E-07 0555 000 278 (241 to 298) 508E-05 278 (188 to 411) 297E-07a
pRBD rs2230288 GBAE365K 2 Multiplicative (HR) 257 (143 to 463) 169E-03 0665 000 mdash mdash 257 (143 to 463) 169E-03a
Age at onset rs34311866 TMEM175M393T
13 Continuous minus072 (minus121 to minus023) 387E-03 0515 000 minus072 (minus083 to minus058) 283E-02 minus072 (minus121 to minus023)
Age at onset rs199347 intron_GPNMB 12 Continuous 070 (027 to 114) 142E-03 0824 000 070 (060 to 077) 112E-02 070 (027 to 114) 142E-03a
HY ge 30 rs76904798 5_LRRK2 13 Multiplicative (HR) 133 (116 to 152) 527E-05 0049 4315 133 (126 to 143) 164E-03 134 (111 to 163) 280E-03a
Family history rs34637584 LRRK2G2019S 8 Multiplicative (OR) 354 (172 to 729) 606E-04 0856 000 353 (278 to 398) 166E-02 354 (172 to 729) 606E-04a
Age at onset rs11060180 intron_CCDC62 13 Continuous 062 (021 to 103) 332E-03 0054 4260 062 (049 to 075) 274E-02 055 (minus000 to 111) 514E-02
Age at onset GRS 13 Continuous minus060 (minus089 minus031) 533E-05 0749 000 minus060 (minus065 minus052) 902E-04 minus060 (minus089 minus031) 533E-05a
Abbreviations FDR = false discovery rate GRS = genetic risk score HR = hazard ratio HY = Hoehn and Yahr scale OR = odds ratio pRBD = possible REM sleep behavior disorderpRBD was only available in 2 cohorts and a leave-one-out analysis was not conducted for this outcomea Significant after FDR adjustment in a random effect model
6NeurologyG
enetics
|Vo
lume5N
umber
4|
Augu
st2019
NeurologyorgN
G
progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
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is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Parkinson disease is one of the most common neurodegen-erative diseases with an estimated lifetime risk as high as1ndash21 Parkinson disease is traditionally characterized bymotor features such as bradykinesia rigidity and tremorHowever in addition to these motor symptoms patients withParkinson disease also develop nonmotor symptoms(NMSs) which include depression cognitive decline sleepabnormalities reduced olfaction and autonomic dysfunc-tion2 Collectively the combined spectrum of motor andNMSs more accurately reflects the multisystem nature of thedisease Patients with Parkinson disease may present withvarious combinations of symptoms and show differences inthe rates of progression3 The application of modern molec-ular genetic approaches over the last decade has revealeda significant number of genetic risk loci for idiopathic Par-kinson disease4ndash7 However in comparison with case-controlgenome-wide association study (GWAS) analyzing how ge-netic factors influence clinical presentation and progressionrequires longitudinal cohorts with much more detailedobservations Such data are sparse and individual cohorts areoften small in size and quite varied posing a challenge both insample size and heterogeneity
In an attempt to address these issues we collected data from13 distinct longitudinal Parkinson disease cohorts with de-tailed clinical data including assessment of disease pro-gression We sought to determine whether Parkinson diseasegenetic risk factors either in the form of known GWAS var-iants or an aggregate genetic risk score (GRS) are associatedwith changes in clinical progression and the disease features
MethodsStudy design and participantsA total of 13 Parkinson disease cohorts from North AmericaEurope and Australia participated in the study Nine wereprospective observational cohorts and the rest were fromrandomized clinical trials The observational cohorts wereDrug Interaction with Genes in Parkinsonrsquos Disease(DIGPD) Harvard Biomarkers Study (HBS) Oslo Parkin-sonrsquos Disease study (partly including retrospective data) TheNorwegian ParkWest study (ParkWest) Parkinsonrsquos DiseaseBiomarker Program (PDBP) Parkinsonism Incidence andCognitive and Non-motor heterogeneity In CambridgeShire(PICNICS) Parkinsonrsquos Progression Markers Initiative
(PPMI) Profiling Parkinsonrsquos disease study (ProPark) andthe Morris K Udall Centers for Parkinsonrsquos Research (Udall)The 4 cohorts from randomized clinical trials were Deprenyland Tocopherol Antioxidative Therapy of Parkinsonism(DATATOP) NIH Exploratory Trials in Parkinsonrsquos DiseaseLarge Simple Study 1 ParkFit study (ParkFit) and ParkinsonResearch Examination of CEP-1347 Trial with a subsequentprospective study (PreCEPTPostCEPT) Information onthese cohorts can be found in appendix e-1 (linkslwwcomNXGA169) Subsets of participants from the cohorts whoprovided DNA and were nonrelated participants with PDdiagnosed at age 18 years or later and of European ancestrywere included in the study Participantsrsquo information andgenetic samples were obtained under appropriate writtenconsent and with local institutional and ethical approvals
Genotyping SNPs and calculation of GRSOslo samples were genotyped on the Illumina InfiniumOmniExpress array DIGPD samples were genotyped byIllumina Multi-Ethnic Genotyping Array and all other sam-ples were genotyped on the NeuroX array8 The qualitycontrol process of variant calling included GenTrain scorelt07 minor allele frequency (MAF) gt005 (for sample qualitycontrol but not in our analysis of rare risk factors) and Hardy-Weinberg equilibrium test statistic gt10minus6 Sample-specificquality control included a sample call rate of gt095 confir-mation of sex through genotyping homozygosity quantifiedby F within plusmn 3 SD from the population mean Europeanancestry confirmed by principal-components analysis with1000 Genomes data as the reference and genetic relatednessof any 2 individuals lt0125 Detailed information regardingNeuroX and the quality control process has been describedpreviously9 In the present study we investigated 31 singlenucleotide polymorphisms (SNPs) previously shown to besignificantly associated with Parkinson disease10ndash12 In addi-tion we also calculated a GRS for each participant based onthese variants The scores were transformed into Z-scoreswithin each cohort and treated as an exposure with effectestimates based on 1 SD change from the population meanThe list of 31 SNPs and the GRS calculation method areprovided in table e-1 (linkslwwcomNXGA170)
Furthermore principal components (PCs) were created foreach data set from genotypes using PLINK For the PC calcu-lation variants were filtered for MAF (gt005) genotype miss-ingness (lt005) and Hardy-Weinberg equilibrium (p ge 10minus5)
GlossaryESS = Epworth Sleepiness Scale FDR = false discovery rate GRS = genetic risk score GWAS = genome-wide associationstudy HR = hazard ratio HY = Hoehn and Yahr scale MAF = minor allele frequency MDS = Movement Disorder SocietyMMSE = Mini-Mental State Examination MoCA = Montreal Cognitive Assessment MSQ = Mayo Sleep QuestionnaireNMS = nonmotor symptom OR = odds ratio PC = principal component PDSS = Parkinsonrsquos Disease Sleep Scale PPMI =Parkinsonrsquos Progression Markers Initiative RBD = rapid eye movement sleep behavior disorder RBDSQ = RBD ScreeningQuestionnaireRLS = restless legs syndrome SEADL = Schwab and England Activities of Daily Living ScaleUPDRS =UnifiedParkinsonrsquos Disease Rating Scale
2 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
The remaining variants were pruned (using a 50-kb windowwith a 5 SNP shift per window and r2 threshold of 05) and PCswere calculated using the pruned variants
MeasurementsThe following clinicalmeasurements and binomial outcomeswererecorded longitudinally (table e-2 linkslwwcomNXGA171)total and subscores of the Unified Parkinsonrsquos Disease RatingScale (UPDRS) or the Movement Disorder Society revisedUPDRS version (MDS-UPDRS) modified Hoehn and Yahrscales (HY) modified Schwab and England Activities of DailyLiving Scale and scores for the Mini-Mental State Examination(MMSE) The SCales for Outcomes in PArkinsons disease(SCOPA)-Cognition and Montreal Cognitive Assessment(MoCA) Each was treated as a continuous outcome For theUPDRS and MDS-UPDRS scores specifically we took Z-scoresof the total and subscores (except for part 4 at baseline) tocompare the original and revised UPDRS versions The conver-sionwas applied to the scores for all subsequent visits ForUPDRSpart 4most participants had very low scores or 0 at baseline sowenormalized across all observations within each cohort We alsoanalyzed binomial outcomes If we had access to the raw data weused common cutoff values which had been tested and reportedspecificity of 85 or more in patientsrsquo population The binomialoutcomes include existence of family history (1st-degree relative1st- and 2nd-degree relatives in HBS PreCEPT ProPark andUdall) hyposmia (University of Pennsylvania Smell IdentificationTest lt 2113 or answering ldquoyesrdquo to question 2 in the NMS ques-tionnaire) cognitive impairment (SCOPA-Cognition lt 23MMSE lt 27 or MoCA lt 241415 or diagnosed with TheDiagnostic and StatisticalManual ofMental Disorders -IV criteria fordementia) wearing off (UPDRSMDS-UPDRSpart 4 off timegt0or physicianrsquos diagnosis) dyskinesia (UPDRSMDS-UPDRS part4 dyskinesia time gt0 or physicianrsquos diagnosis) depression (BeckDepression Inventory gt 14 [PICNICS used 9 instead of 14]HamiltonDepression Rating Scale gt9 Geriatric Depression Scale[GRS] gt 516 or physicianrsquos diagnosis) constipation (MDS-UPDRS part 1 item 11 gt 0 or answering ldquoyesrdquo to question 5 inthe NMS questionnaire) excessive daytime sleepiness (Epworthsleepiness scale gt 917 insomnia [MDS-UPDRS part 1 item 7 gt0] rapid eye movement sleep behavior disorder [RBD]) (an-swered ldquoyesrdquo to question 1 on the Mayo Sleep Questionnaire[MSQ]18 or RBD screening questionnaire [RBDSQ gt5]19
restless legs syndrome [RLS]) (answered ldquoyesrdquo to MSQ ques-tion 320 or RLS diagnosis positive by RBDSQ) and the pro-gression to HY ge 3 (HY3 representing moderate to severedisease) The individual definitions of these binomial outcomesare summarized in table e-2 (linkslwwcomNXGA171) Agesex years of education age at motor symptom onset andwhether the patient was treated with levodopa or dopamineagonists at each visit were also recorded for adjustments
Statistical analysis
Cohort-level analysisWe analyzed the association between exposures and out-comes using appropriate additive models Covariates of in-terest were not available for all cohorts therefore the model
specifications were slightly different between cohorts (de-tailed in table e-3 linkslwwcomNXGA172) Briefly theassociations between an SNPGRS and age at onset wereanalyzed by linear regression modeling adjusting for pop-ulation stratification (PC1 and PC2) The association be-tween family history of Parkinson disease and SNPGRS wasanalyzed with a logistic regression model adjusting for PC12For continuous variables linear regressionmodeling adjustingfor sex education PC12 age at onset years from diagnosisfamily history and treatment status was applied For thosewho had multiple observations random intercept was addedto adjust for repeated measurements of the same individualFor binomial outcomes the logistic regression at baselineobservation was applied using the same covariates as thecontinuous models Those that were negative at baseline werefurther analyzed by a Cox regression with the same covariatesbut with treatment status as a time-varying covariate Obser-vations with missing variables were excluded from the analyses
Meta-analysisWe applied inverse weighting (precision method) for eachcombination of outcome-predictor association and combinedthe estimates from the 13 different cohorts in a fixed effectmodel Multiple test correction for SNPs was controlled withan overall false discovery rate (FDR) of 005 per outcomebeing considered significant Similarly multiple testing ofoutcomes for GRS was corrected with an FDR of 005 butacross all traits In addition as a test of homogeneity I2 indicesand forest plots were used for quantitative assessment Asa sensitivity analysis we conducted up to 13 iterations of themeta-analyses for the 12 cohorts excluding each cohort periteration This analysis provides information regarding het-erogeneity of the cohorts and how one specific cohort ex-clusion affects the results The range of estimates andmaximum p values for the iterations were included Finally weconducted the 13-cohort meta-analysis in a random effectsmodel with restricted maximum likelihood estimation usingthe same multiple testing correction
All the above analyses were conducted with PLINK version 19and R version 344 (64-bit) Statistical tests were all 2 sided
Data availabilityQualified investigators can request raw data through theorganizationsrsquo homepages (PDBP pdbpnindsnihgovPPMI ppmi-infoorg) or collaboration
ResultsA total of 23423 visits by 4307 patients with a median follow-up period of 297 years (quartile range of [163ndash494] years)were eligible for the analysis The baseline characteristics ofthe cohorts are shown in table 1 The mean ages at onsetvaried from 54 to 69 years the average disease durations atcohort entry ranged from less than 1 to 10 years and themeanobservation periods were between 12 and 68 years AllDATATOP ParkWest PPMI and PreCEPT participants
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 3
Table 1 Summary characteristics of 13 cohorts
DATATOP DIGPD HBSNET-PDLS1 Oslo ParkFit ParkWest PDBP PICNICS PPMI
PreCEPTPostCEPT ProPark Udall
Cohort size n 440 311 580 406 317 335 150 422 120 357 321 296 252
Follow-upduration y
122 (041) 219 (151) 153 (087) 448 (145) 464 (310) 197 (000) 304 (009) 206 (170) 304 (163) 487 (135) 679 (095) 462 (114) 377 (181)
Female n () 146 (332) 121 (389) 201 (347) 148 (365) 107 (338) 110 (328) 57 (380) 174 (412) 43 (358) 121 (339) 106 (330) 105 (355) 73 (290)
Family historyn ()
86 (209) 69 (223) 148 (255) 59 (145) 43 (140) mdash 17 (113) 54 (128) 19 (158) 48 (135) 93 (292) 76 (259) 71 (284)
Age at onset y 5865 (917) 5941 (980) 6216 (1046) 6064 (945) 5433 (1006) 6079 (865) 6727 (926) 5851 (1028) 6894 (934) 6145 (955) 5947 (922) 5314 (1060) 6426 (864)
Baseline fromdiagnosis y
114 (117) 260 (157) 409 (463) 150 (100) 1013 (604) 518 (444) 013 (012) 568 (564) 023 (048) 054 (054) 080 (083) 656 (467) 621 (538)
Levodopa usen ()
0 (00) 198 (639) 415 (716) 207 (512) mdash mdash 0 (00) 255 (604) 36 (300) 0 (00) 0 (00) 202 (682) 215 (853)
Dopamineagonist use n ()
0 (00) 228 (733) 224 (386) 280 (693) mdash mdash 0 (00) 61 (145) 22 (183) 0 (00) 1 (03) 222 (750) 118 (468)
Modified HY 161 (053) 175 (055) 214 (064) mdash 219 (064) 208 (033) 186 (058) 204 (069) 164 (067) 155 (050) 175 (048) 251 (079) 229 (068)
UPDRS1 mdash 769 (450) 170 (159) 131 (145) mdash mdash 195 (176) 990 (611) mdash 540 (397) 084 (119) mdash 192 (199)
UPDRS2 mdash 772 (466) 921 (523) 729 (386) mdash mdash 819 (422) 1114 (801) mdash 580 (411) 611 (320) mdash 1074 (713)
UPDRS3 mdash 2037 (1023) 1930 (958) 1777 (832) 1542 (1030) mdash 2209 (977) 2364 (1308) mdash 2088 (900) 1869 (765) mdash 2292 (1109)
UPDRS4 mdash 066 (256) 225 (205) 134 (149) mdash mdash 057 (114) 220 (317) mdash mdash mdash mdash 202 (275)
MDS_UPDRS total mdash 3643 (1602) mdash mdash mdash mdash mdash 4688 (2404) 4727 (1797) mdash mdash mdash mdash
UPDRS total 2468 (1156) mdash 3233 (1428) 2767 (1162) mdash 3211 (1010) 3279 (1391) mdash mdash mdash 2539 (1010) mdash 3264 (1828)
MMSE 2899 (135) 2838 (173) 2835 (217) mdash mdash 2809 (161) 2788 (227) mdash 2871 (143) mdash 2929 (107) 2705 (250) 2683 (350)
MoCA mdash mdash mdash mdash mdash mdash mdash 2544 (340) mdash 2717 (223) mdash mdash 2437 (363)
SEADL 9155 (649) 8055 (2902) mdash 9159 (606) mdash mdash 8940 (735) 8511 (1310) mdash 9318 (591) 9277 (526) mdash 8053 (1756)
Hyposmia n () mdash 89 (289) mdash mdash mdash mdash 54 (360) 276 (654) mdash 164 (459) mdash 173 (638) 69 (670)
Cognitiveimpairment n ()
26 (59) 3 (10) 74 (130) 29 (71) mdash 55 (164) 27 (180) 96 (227) 11 (92) 28 (78) 3 (09) 77 (270) 29 (115)
Motorfluctuation n ()
mdash 40 (129) 228 (399) 103 (254) mdash mdash 4 (27) 129 (481) 1 (08) mdash mdash 94 (324) 75 (354)
Dyskinesia n () 4 (09) 13 (42) 207 (362) 5 (12) mdash mdash 2 (13) 196 (464) 0 (00) mdash mdash 81 (276) 44 (228)
Continued
4NeurologyG
enetics
|Vo
lume5N
umber
4|
Augu
st2019
NeurologyorgN
G
were dopaminergic therapy naive at baseline patients in theother cohorts were not In the primary analysis of 13 cohorts17 associations were identified as significant after FDR cor-rection (table 2 and more information in table e-4 linkslwwcomNXGA173) Overwhelmingly 10 were associated withGBA variants In particular GBA pE365K (rs2230288) wasassociated with 237- (153ndash366) (95 CI) fold higher oddsof having cognitive impairment at baseline (p = 109 times 10minus4)and 278- (188ndash411) fold higher hazard ratio (HR) of de-veloping cognitive impairment during follow-up among thosewho were negative for cognitive impairment at baseline (p =297 times 10minus7) This SNPwas also associated with a higher meanon the HY at 010 (004ndash016) (p = 153 times 10minus3) but the testof homogeneity was rejected (p= 0017 I2 = 489) In additionit was associated with the development of an RBD among thosewho did not have the disorder at baseline OtherGBAmutationspN370S (rs767763715) and pT408M (rs75548401) wereboth associated with a higher HR of reaching HY3 (459[260ndash810] for pN370S [p = 158 times 10minus7] and 193 [134ndash278]for pT408M [p = 440 times 10minus4]) GBA pN370N was also as-sociated with a higher risk of developing wearing-off dyskinesiaand daytime sleepiness pT408M was associated with a 648(204ndash2060) times higher odds ratio (OR) of having an RBDsymptom at baseline (p = 153 times 10minus3)
Two LRRK2 variants in our 31 SNPs of interest were signifi-cantly associated with outcomes LRRK2 pG2019S(rs34637584) was associated with higher odds of having a familyhistory of Parkinson disease (OR 354 [172ndash729] p = 606 times10minus4) and the T allele of rs76904798 (intergenic at the 59 end ofLRRK2) was associated with a higher HR of reaching HY3 (HR133 [116ndash152] for the T allele p = 527 times 10minus5)
Age at onset was inversely associated with theZ value of the GRS(minus060 [minus089 to minus031] years per +1 SD p = 533 times 10minus5)Moreover it was associated with rs34311866 (TMEM175pM393T) theC allele of rs199347 (intronic region ofGPNMB)and the G allele of rs1106180 (intronic region of CCDC62)
The majority (1417) of associations showed good accordacross cohorts (I2 lt 50) and the forest plots (figures 1ndash3) alsoillustrate this qualitatively Furthermore up to 13 iterations of theleave-one-out analysis assessed 15 associations of which out-comes were measured in more than 2 cohorts and showeda small range of betas Themaximum p value of 13 iterations wasless than 005 for all associations except for rs114138769 (intronof PMVK) and rs76763715 (GBA pN370S) for wearing-off Ameta-analysis with a random effect model also detected 9 asso-ciations after the same FDR correction although the model ismore conservative than a fixed model
DiscussionWe conducted a meta-analysis with 13 longitudinal patientcohorts and identified multiple associations between geno-types and clinical phenotypic characteristics includingTa
ble
1Su
mmarych
arac
teristicsof13
cohorts(con
tinue
d)
DATA
TOP
DIG
PD
HBS
NET
-PD
LS1
Oslo
Park
Fit
Park
West
PDBP
PICNICS
PPMI
Pre
CEP
TPostCEP
TPro
Park
Udall
Depre
ssionn
()
12(27)
97(316)
35(109)
40(99)
mdashmdash
20(133)
49(116)
27(225)
113(317)
73(227)
48(163)
63(250)
RLS
n(
)mdash
44(145)
37(109)
mdashmdash
mdashmdash
91(233)
mdash23
(64)
mdashmdash
mdash
Con
stipationn
()
9(20)
62(203)
mdashmdash
mdashmdash
17(113)
239(566)
29(242)
113(317)
mdash13
8(466)
mdash
RBDn
()
mdashmdash
mdashmdash
mdashmdash
mdash19
7(505)
mdash93
(261)
mdashmdash
mdash
Daytim
esleepinessn
()
5(11)
138(448)
mdashmdash
mdashmdash
25(167)
165(391)
25(208)
55(154)
mdash12
6(426)
mdash
Inso
mnian
()
11(25)
107(351)
202(351)
mdashmdash
mdash45
(300)
295(699)
62(517)
78(218)
mdash83
(280)
mdash
HYge30
n(
)0(00)
4(13)
71(124)
12(30)
22(145)
17(51)
11(73)
71(168)
13(108)
1(03)
0(00)
117(408)
57(230)
AbbreviationsDATA
TOP=Dep
renyl
andTo
copher
olA
ntioxidativeTh
erap
yofParkinso
nismD
IGPD=Dru
gInteractionwithGen
esin
Par
kinso
nrsquosDisea
seH
BS=Har
vard
Biomarke
rsStudy
HY=Hoeh
nan
dYa
hrscale
MDS=Move
men
tDisord
erSo
cietyMMSE
=Mini-Men
talS
tate
ExaminationM
oCA=Montrea
lCogn
itiveAsses
smentNET-PDLS
=NIH
Exploratory
Trialsin
Parkinso
nrsquosDisea
seLa
rgeSimple
Study1
Oslo=OsloPDstudy
ParkFit=ParkFitstudy
ParkWes
t=theNorw
egianParkWes
tstudy
PDBP=Par
kinso
nrsquosDisea
seBiomarker
Pro
gram
PICNICS=Parkinso
nismInciden
cean
dCogn
itivean
dNon-m
otorhetero
geneity
InCam
bridge
Shire
PPMI=
Parkinso
nrsquosPro
gres
sionMarke
rsInitiative
Pro
Park=Pro
filin
gParkinso
nrsquosDisea
sestudy
RBD=REM
slee
pbeh
aviordisord
erR
LS=restless
legs
syndro
me
SEADL=Sc
hwab
andEn
glan
dActivitiesofDaily
Living
Scale
UPDRS=UnifiedParkinso
nrsquosDisea
seRatingSc
ale
Continuousva
riab
lesweresu
mmarized
asmea
n(SD)
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 5
Table 2 Meta-analysis for 13 cohorts and the results of sensitivity analysis
Outcome rsNo
Known geneor nearestgene
No ofcohorts
Scale of theeffect
Fixed effect model
Test ofhomogeneity I2 ()
Leave-one-out analysis Random effect model
Estimate (95 CI) pEstimate (Min toMax) Max p Estimate (95 CI) p
Wearing-off rs114138760 intron_PMVK 9 Multiplicative (HR) 166 (119 to 231) 262E-03 0322 1258 166 (144 to 181) 622E-02 165 (114 to 238) 739E-03
Dyskinesia rs76763715 GBAN370S 8 Multiplicative (HR) 301 (181 to 501) 217E-05 0011 6053 300 (198 to 405) 226E-02 249 (106 to 586) 373E-02
HY ge 30 rs76763715 GBAN370S 6 Multiplicative (HR) 459 (260 to 810) 158E-07 0654 000 459 (402 to 541) 200E-05 459 (260 to 810) 158E-07a
Wearing-off rs76763715 GBAN370S 6 Multiplicative (HR) 203 (128 to 321) 256E-03 0021 6270 202 (161 to 265) 867E-02 192 (085 to 433) 114E-01
Daytimesleepiness
rs76763715 GBAN370S 6 Multiplicative (HR) 328 (169 to 634) 424E-04 0467 000 330 (285 to 438) 375E-03 328 (169 to 634) 424E-04a
HY ge 30 rs75548401 GBAT408M 8 Multiplicative (HR) 193 (134 to 278) 440E-04 0208 3243 193 (170 to 241) 108E-02 196 (122 to 314) 522E-03
pRBD (baseline) rs75548401 GBAT408M 2 Multiplicative (OR) 648 (204 to 2060) 153E-03 0118 5906 mdash mdash 625 (102 to 3820) 472E-02
HY rs2230288 GBAE365K 12 Continuous 010 (004 to 016) 153E-03 0017 4890 010 (008 to 011) 102E-02 011 (002 to 021) 188E-02
Cognitiveimpairment(baseline)
rs2230288 GBAE365K 8 Multiplicative (OR) 237 (153 to 366) 109E-04 0794 000 237 (220 to 259) 857E-04 237 (153 to 366) 109E-04a
Cognitiveimpairment
rs2230288 GBAE365K 9 Multiplicative (HR) 278 (188 to 411) 297E-07 0555 000 278 (241 to 298) 508E-05 278 (188 to 411) 297E-07a
pRBD rs2230288 GBAE365K 2 Multiplicative (HR) 257 (143 to 463) 169E-03 0665 000 mdash mdash 257 (143 to 463) 169E-03a
Age at onset rs34311866 TMEM175M393T
13 Continuous minus072 (minus121 to minus023) 387E-03 0515 000 minus072 (minus083 to minus058) 283E-02 minus072 (minus121 to minus023)
Age at onset rs199347 intron_GPNMB 12 Continuous 070 (027 to 114) 142E-03 0824 000 070 (060 to 077) 112E-02 070 (027 to 114) 142E-03a
HY ge 30 rs76904798 5_LRRK2 13 Multiplicative (HR) 133 (116 to 152) 527E-05 0049 4315 133 (126 to 143) 164E-03 134 (111 to 163) 280E-03a
Family history rs34637584 LRRK2G2019S 8 Multiplicative (OR) 354 (172 to 729) 606E-04 0856 000 353 (278 to 398) 166E-02 354 (172 to 729) 606E-04a
Age at onset rs11060180 intron_CCDC62 13 Continuous 062 (021 to 103) 332E-03 0054 4260 062 (049 to 075) 274E-02 055 (minus000 to 111) 514E-02
Age at onset GRS 13 Continuous minus060 (minus089 minus031) 533E-05 0749 000 minus060 (minus065 minus052) 902E-04 minus060 (minus089 minus031) 533E-05a
Abbreviations FDR = false discovery rate GRS = genetic risk score HR = hazard ratio HY = Hoehn and Yahr scale OR = odds ratio pRBD = possible REM sleep behavior disorderpRBD was only available in 2 cohorts and a leave-one-out analysis was not conducted for this outcomea Significant after FDR adjustment in a random effect model
6NeurologyG
enetics
|Vo
lume5N
umber
4|
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st2019
NeurologyorgN
G
progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
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is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
The remaining variants were pruned (using a 50-kb windowwith a 5 SNP shift per window and r2 threshold of 05) and PCswere calculated using the pruned variants
MeasurementsThe following clinicalmeasurements and binomial outcomeswererecorded longitudinally (table e-2 linkslwwcomNXGA171)total and subscores of the Unified Parkinsonrsquos Disease RatingScale (UPDRS) or the Movement Disorder Society revisedUPDRS version (MDS-UPDRS) modified Hoehn and Yahrscales (HY) modified Schwab and England Activities of DailyLiving Scale and scores for the Mini-Mental State Examination(MMSE) The SCales for Outcomes in PArkinsons disease(SCOPA)-Cognition and Montreal Cognitive Assessment(MoCA) Each was treated as a continuous outcome For theUPDRS and MDS-UPDRS scores specifically we took Z-scoresof the total and subscores (except for part 4 at baseline) tocompare the original and revised UPDRS versions The conver-sionwas applied to the scores for all subsequent visits ForUPDRSpart 4most participants had very low scores or 0 at baseline sowenormalized across all observations within each cohort We alsoanalyzed binomial outcomes If we had access to the raw data weused common cutoff values which had been tested and reportedspecificity of 85 or more in patientsrsquo population The binomialoutcomes include existence of family history (1st-degree relative1st- and 2nd-degree relatives in HBS PreCEPT ProPark andUdall) hyposmia (University of Pennsylvania Smell IdentificationTest lt 2113 or answering ldquoyesrdquo to question 2 in the NMS ques-tionnaire) cognitive impairment (SCOPA-Cognition lt 23MMSE lt 27 or MoCA lt 241415 or diagnosed with TheDiagnostic and StatisticalManual ofMental Disorders -IV criteria fordementia) wearing off (UPDRSMDS-UPDRSpart 4 off timegt0or physicianrsquos diagnosis) dyskinesia (UPDRSMDS-UPDRS part4 dyskinesia time gt0 or physicianrsquos diagnosis) depression (BeckDepression Inventory gt 14 [PICNICS used 9 instead of 14]HamiltonDepression Rating Scale gt9 Geriatric Depression Scale[GRS] gt 516 or physicianrsquos diagnosis) constipation (MDS-UPDRS part 1 item 11 gt 0 or answering ldquoyesrdquo to question 5 inthe NMS questionnaire) excessive daytime sleepiness (Epworthsleepiness scale gt 917 insomnia [MDS-UPDRS part 1 item 7 gt0] rapid eye movement sleep behavior disorder [RBD]) (an-swered ldquoyesrdquo to question 1 on the Mayo Sleep Questionnaire[MSQ]18 or RBD screening questionnaire [RBDSQ gt5]19
restless legs syndrome [RLS]) (answered ldquoyesrdquo to MSQ ques-tion 320 or RLS diagnosis positive by RBDSQ) and the pro-gression to HY ge 3 (HY3 representing moderate to severedisease) The individual definitions of these binomial outcomesare summarized in table e-2 (linkslwwcomNXGA171) Agesex years of education age at motor symptom onset andwhether the patient was treated with levodopa or dopamineagonists at each visit were also recorded for adjustments
Statistical analysis
Cohort-level analysisWe analyzed the association between exposures and out-comes using appropriate additive models Covariates of in-terest were not available for all cohorts therefore the model
specifications were slightly different between cohorts (de-tailed in table e-3 linkslwwcomNXGA172) Briefly theassociations between an SNPGRS and age at onset wereanalyzed by linear regression modeling adjusting for pop-ulation stratification (PC1 and PC2) The association be-tween family history of Parkinson disease and SNPGRS wasanalyzed with a logistic regression model adjusting for PC12For continuous variables linear regressionmodeling adjustingfor sex education PC12 age at onset years from diagnosisfamily history and treatment status was applied For thosewho had multiple observations random intercept was addedto adjust for repeated measurements of the same individualFor binomial outcomes the logistic regression at baselineobservation was applied using the same covariates as thecontinuous models Those that were negative at baseline werefurther analyzed by a Cox regression with the same covariatesbut with treatment status as a time-varying covariate Obser-vations with missing variables were excluded from the analyses
Meta-analysisWe applied inverse weighting (precision method) for eachcombination of outcome-predictor association and combinedthe estimates from the 13 different cohorts in a fixed effectmodel Multiple test correction for SNPs was controlled withan overall false discovery rate (FDR) of 005 per outcomebeing considered significant Similarly multiple testing ofoutcomes for GRS was corrected with an FDR of 005 butacross all traits In addition as a test of homogeneity I2 indicesand forest plots were used for quantitative assessment Asa sensitivity analysis we conducted up to 13 iterations of themeta-analyses for the 12 cohorts excluding each cohort periteration This analysis provides information regarding het-erogeneity of the cohorts and how one specific cohort ex-clusion affects the results The range of estimates andmaximum p values for the iterations were included Finally weconducted the 13-cohort meta-analysis in a random effectsmodel with restricted maximum likelihood estimation usingthe same multiple testing correction
All the above analyses were conducted with PLINK version 19and R version 344 (64-bit) Statistical tests were all 2 sided
Data availabilityQualified investigators can request raw data through theorganizationsrsquo homepages (PDBP pdbpnindsnihgovPPMI ppmi-infoorg) or collaboration
ResultsA total of 23423 visits by 4307 patients with a median follow-up period of 297 years (quartile range of [163ndash494] years)were eligible for the analysis The baseline characteristics ofthe cohorts are shown in table 1 The mean ages at onsetvaried from 54 to 69 years the average disease durations atcohort entry ranged from less than 1 to 10 years and themeanobservation periods were between 12 and 68 years AllDATATOP ParkWest PPMI and PreCEPT participants
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 3
Table 1 Summary characteristics of 13 cohorts
DATATOP DIGPD HBSNET-PDLS1 Oslo ParkFit ParkWest PDBP PICNICS PPMI
PreCEPTPostCEPT ProPark Udall
Cohort size n 440 311 580 406 317 335 150 422 120 357 321 296 252
Follow-upduration y
122 (041) 219 (151) 153 (087) 448 (145) 464 (310) 197 (000) 304 (009) 206 (170) 304 (163) 487 (135) 679 (095) 462 (114) 377 (181)
Female n () 146 (332) 121 (389) 201 (347) 148 (365) 107 (338) 110 (328) 57 (380) 174 (412) 43 (358) 121 (339) 106 (330) 105 (355) 73 (290)
Family historyn ()
86 (209) 69 (223) 148 (255) 59 (145) 43 (140) mdash 17 (113) 54 (128) 19 (158) 48 (135) 93 (292) 76 (259) 71 (284)
Age at onset y 5865 (917) 5941 (980) 6216 (1046) 6064 (945) 5433 (1006) 6079 (865) 6727 (926) 5851 (1028) 6894 (934) 6145 (955) 5947 (922) 5314 (1060) 6426 (864)
Baseline fromdiagnosis y
114 (117) 260 (157) 409 (463) 150 (100) 1013 (604) 518 (444) 013 (012) 568 (564) 023 (048) 054 (054) 080 (083) 656 (467) 621 (538)
Levodopa usen ()
0 (00) 198 (639) 415 (716) 207 (512) mdash mdash 0 (00) 255 (604) 36 (300) 0 (00) 0 (00) 202 (682) 215 (853)
Dopamineagonist use n ()
0 (00) 228 (733) 224 (386) 280 (693) mdash mdash 0 (00) 61 (145) 22 (183) 0 (00) 1 (03) 222 (750) 118 (468)
Modified HY 161 (053) 175 (055) 214 (064) mdash 219 (064) 208 (033) 186 (058) 204 (069) 164 (067) 155 (050) 175 (048) 251 (079) 229 (068)
UPDRS1 mdash 769 (450) 170 (159) 131 (145) mdash mdash 195 (176) 990 (611) mdash 540 (397) 084 (119) mdash 192 (199)
UPDRS2 mdash 772 (466) 921 (523) 729 (386) mdash mdash 819 (422) 1114 (801) mdash 580 (411) 611 (320) mdash 1074 (713)
UPDRS3 mdash 2037 (1023) 1930 (958) 1777 (832) 1542 (1030) mdash 2209 (977) 2364 (1308) mdash 2088 (900) 1869 (765) mdash 2292 (1109)
UPDRS4 mdash 066 (256) 225 (205) 134 (149) mdash mdash 057 (114) 220 (317) mdash mdash mdash mdash 202 (275)
MDS_UPDRS total mdash 3643 (1602) mdash mdash mdash mdash mdash 4688 (2404) 4727 (1797) mdash mdash mdash mdash
UPDRS total 2468 (1156) mdash 3233 (1428) 2767 (1162) mdash 3211 (1010) 3279 (1391) mdash mdash mdash 2539 (1010) mdash 3264 (1828)
MMSE 2899 (135) 2838 (173) 2835 (217) mdash mdash 2809 (161) 2788 (227) mdash 2871 (143) mdash 2929 (107) 2705 (250) 2683 (350)
MoCA mdash mdash mdash mdash mdash mdash mdash 2544 (340) mdash 2717 (223) mdash mdash 2437 (363)
SEADL 9155 (649) 8055 (2902) mdash 9159 (606) mdash mdash 8940 (735) 8511 (1310) mdash 9318 (591) 9277 (526) mdash 8053 (1756)
Hyposmia n () mdash 89 (289) mdash mdash mdash mdash 54 (360) 276 (654) mdash 164 (459) mdash 173 (638) 69 (670)
Cognitiveimpairment n ()
26 (59) 3 (10) 74 (130) 29 (71) mdash 55 (164) 27 (180) 96 (227) 11 (92) 28 (78) 3 (09) 77 (270) 29 (115)
Motorfluctuation n ()
mdash 40 (129) 228 (399) 103 (254) mdash mdash 4 (27) 129 (481) 1 (08) mdash mdash 94 (324) 75 (354)
Dyskinesia n () 4 (09) 13 (42) 207 (362) 5 (12) mdash mdash 2 (13) 196 (464) 0 (00) mdash mdash 81 (276) 44 (228)
Continued
4NeurologyG
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were dopaminergic therapy naive at baseline patients in theother cohorts were not In the primary analysis of 13 cohorts17 associations were identified as significant after FDR cor-rection (table 2 and more information in table e-4 linkslwwcomNXGA173) Overwhelmingly 10 were associated withGBA variants In particular GBA pE365K (rs2230288) wasassociated with 237- (153ndash366) (95 CI) fold higher oddsof having cognitive impairment at baseline (p = 109 times 10minus4)and 278- (188ndash411) fold higher hazard ratio (HR) of de-veloping cognitive impairment during follow-up among thosewho were negative for cognitive impairment at baseline (p =297 times 10minus7) This SNPwas also associated with a higher meanon the HY at 010 (004ndash016) (p = 153 times 10minus3) but the testof homogeneity was rejected (p= 0017 I2 = 489) In additionit was associated with the development of an RBD among thosewho did not have the disorder at baseline OtherGBAmutationspN370S (rs767763715) and pT408M (rs75548401) wereboth associated with a higher HR of reaching HY3 (459[260ndash810] for pN370S [p = 158 times 10minus7] and 193 [134ndash278]for pT408M [p = 440 times 10minus4]) GBA pN370N was also as-sociated with a higher risk of developing wearing-off dyskinesiaand daytime sleepiness pT408M was associated with a 648(204ndash2060) times higher odds ratio (OR) of having an RBDsymptom at baseline (p = 153 times 10minus3)
Two LRRK2 variants in our 31 SNPs of interest were signifi-cantly associated with outcomes LRRK2 pG2019S(rs34637584) was associated with higher odds of having a familyhistory of Parkinson disease (OR 354 [172ndash729] p = 606 times10minus4) and the T allele of rs76904798 (intergenic at the 59 end ofLRRK2) was associated with a higher HR of reaching HY3 (HR133 [116ndash152] for the T allele p = 527 times 10minus5)
Age at onset was inversely associated with theZ value of the GRS(minus060 [minus089 to minus031] years per +1 SD p = 533 times 10minus5)Moreover it was associated with rs34311866 (TMEM175pM393T) theC allele of rs199347 (intronic region ofGPNMB)and the G allele of rs1106180 (intronic region of CCDC62)
The majority (1417) of associations showed good accordacross cohorts (I2 lt 50) and the forest plots (figures 1ndash3) alsoillustrate this qualitatively Furthermore up to 13 iterations of theleave-one-out analysis assessed 15 associations of which out-comes were measured in more than 2 cohorts and showeda small range of betas Themaximum p value of 13 iterations wasless than 005 for all associations except for rs114138769 (intronof PMVK) and rs76763715 (GBA pN370S) for wearing-off Ameta-analysis with a random effect model also detected 9 asso-ciations after the same FDR correction although the model ismore conservative than a fixed model
DiscussionWe conducted a meta-analysis with 13 longitudinal patientcohorts and identified multiple associations between geno-types and clinical phenotypic characteristics includingTa
ble
1Su
mmarych
arac
teristicsof13
cohorts(con
tinue
d)
DATA
TOP
DIG
PD
HBS
NET
-PD
LS1
Oslo
Park
Fit
Park
West
PDBP
PICNICS
PPMI
Pre
CEP
TPostCEP
TPro
Park
Udall
Depre
ssionn
()
12(27)
97(316)
35(109)
40(99)
mdashmdash
20(133)
49(116)
27(225)
113(317)
73(227)
48(163)
63(250)
RLS
n(
)mdash
44(145)
37(109)
mdashmdash
mdashmdash
91(233)
mdash23
(64)
mdashmdash
mdash
Con
stipationn
()
9(20)
62(203)
mdashmdash
mdashmdash
17(113)
239(566)
29(242)
113(317)
mdash13
8(466)
mdash
RBDn
()
mdashmdash
mdashmdash
mdashmdash
mdash19
7(505)
mdash93
(261)
mdashmdash
mdash
Daytim
esleepinessn
()
5(11)
138(448)
mdashmdash
mdashmdash
25(167)
165(391)
25(208)
55(154)
mdash12
6(426)
mdash
Inso
mnian
()
11(25)
107(351)
202(351)
mdashmdash
mdash45
(300)
295(699)
62(517)
78(218)
mdash83
(280)
mdash
HYge30
n(
)0(00)
4(13)
71(124)
12(30)
22(145)
17(51)
11(73)
71(168)
13(108)
1(03)
0(00)
117(408)
57(230)
AbbreviationsDATA
TOP=Dep
renyl
andTo
copher
olA
ntioxidativeTh
erap
yofParkinso
nismD
IGPD=Dru
gInteractionwithGen
esin
Par
kinso
nrsquosDisea
seH
BS=Har
vard
Biomarke
rsStudy
HY=Hoeh
nan
dYa
hrscale
MDS=Move
men
tDisord
erSo
cietyMMSE
=Mini-Men
talS
tate
ExaminationM
oCA=Montrea
lCogn
itiveAsses
smentNET-PDLS
=NIH
Exploratory
Trialsin
Parkinso
nrsquosDisea
seLa
rgeSimple
Study1
Oslo=OsloPDstudy
ParkFit=ParkFitstudy
ParkWes
t=theNorw
egianParkWes
tstudy
PDBP=Par
kinso
nrsquosDisea
seBiomarker
Pro
gram
PICNICS=Parkinso
nismInciden
cean
dCogn
itivean
dNon-m
otorhetero
geneity
InCam
bridge
Shire
PPMI=
Parkinso
nrsquosPro
gres
sionMarke
rsInitiative
Pro
Park=Pro
filin
gParkinso
nrsquosDisea
sestudy
RBD=REM
slee
pbeh
aviordisord
erR
LS=restless
legs
syndro
me
SEADL=Sc
hwab
andEn
glan
dActivitiesofDaily
Living
Scale
UPDRS=UnifiedParkinso
nrsquosDisea
seRatingSc
ale
Continuousva
riab
lesweresu
mmarized
asmea
n(SD)
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 5
Table 2 Meta-analysis for 13 cohorts and the results of sensitivity analysis
Outcome rsNo
Known geneor nearestgene
No ofcohorts
Scale of theeffect
Fixed effect model
Test ofhomogeneity I2 ()
Leave-one-out analysis Random effect model
Estimate (95 CI) pEstimate (Min toMax) Max p Estimate (95 CI) p
Wearing-off rs114138760 intron_PMVK 9 Multiplicative (HR) 166 (119 to 231) 262E-03 0322 1258 166 (144 to 181) 622E-02 165 (114 to 238) 739E-03
Dyskinesia rs76763715 GBAN370S 8 Multiplicative (HR) 301 (181 to 501) 217E-05 0011 6053 300 (198 to 405) 226E-02 249 (106 to 586) 373E-02
HY ge 30 rs76763715 GBAN370S 6 Multiplicative (HR) 459 (260 to 810) 158E-07 0654 000 459 (402 to 541) 200E-05 459 (260 to 810) 158E-07a
Wearing-off rs76763715 GBAN370S 6 Multiplicative (HR) 203 (128 to 321) 256E-03 0021 6270 202 (161 to 265) 867E-02 192 (085 to 433) 114E-01
Daytimesleepiness
rs76763715 GBAN370S 6 Multiplicative (HR) 328 (169 to 634) 424E-04 0467 000 330 (285 to 438) 375E-03 328 (169 to 634) 424E-04a
HY ge 30 rs75548401 GBAT408M 8 Multiplicative (HR) 193 (134 to 278) 440E-04 0208 3243 193 (170 to 241) 108E-02 196 (122 to 314) 522E-03
pRBD (baseline) rs75548401 GBAT408M 2 Multiplicative (OR) 648 (204 to 2060) 153E-03 0118 5906 mdash mdash 625 (102 to 3820) 472E-02
HY rs2230288 GBAE365K 12 Continuous 010 (004 to 016) 153E-03 0017 4890 010 (008 to 011) 102E-02 011 (002 to 021) 188E-02
Cognitiveimpairment(baseline)
rs2230288 GBAE365K 8 Multiplicative (OR) 237 (153 to 366) 109E-04 0794 000 237 (220 to 259) 857E-04 237 (153 to 366) 109E-04a
Cognitiveimpairment
rs2230288 GBAE365K 9 Multiplicative (HR) 278 (188 to 411) 297E-07 0555 000 278 (241 to 298) 508E-05 278 (188 to 411) 297E-07a
pRBD rs2230288 GBAE365K 2 Multiplicative (HR) 257 (143 to 463) 169E-03 0665 000 mdash mdash 257 (143 to 463) 169E-03a
Age at onset rs34311866 TMEM175M393T
13 Continuous minus072 (minus121 to minus023) 387E-03 0515 000 minus072 (minus083 to minus058) 283E-02 minus072 (minus121 to minus023)
Age at onset rs199347 intron_GPNMB 12 Continuous 070 (027 to 114) 142E-03 0824 000 070 (060 to 077) 112E-02 070 (027 to 114) 142E-03a
HY ge 30 rs76904798 5_LRRK2 13 Multiplicative (HR) 133 (116 to 152) 527E-05 0049 4315 133 (126 to 143) 164E-03 134 (111 to 163) 280E-03a
Family history rs34637584 LRRK2G2019S 8 Multiplicative (OR) 354 (172 to 729) 606E-04 0856 000 353 (278 to 398) 166E-02 354 (172 to 729) 606E-04a
Age at onset rs11060180 intron_CCDC62 13 Continuous 062 (021 to 103) 332E-03 0054 4260 062 (049 to 075) 274E-02 055 (minus000 to 111) 514E-02
Age at onset GRS 13 Continuous minus060 (minus089 minus031) 533E-05 0749 000 minus060 (minus065 minus052) 902E-04 minus060 (minus089 minus031) 533E-05a
Abbreviations FDR = false discovery rate GRS = genetic risk score HR = hazard ratio HY = Hoehn and Yahr scale OR = odds ratio pRBD = possible REM sleep behavior disorderpRBD was only available in 2 cohorts and a leave-one-out analysis was not conducted for this outcomea Significant after FDR adjustment in a random effect model
6NeurologyG
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progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
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httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
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nextAn erratum has been published regarding this article Please see
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httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
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httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Table 1 Summary characteristics of 13 cohorts
DATATOP DIGPD HBSNET-PDLS1 Oslo ParkFit ParkWest PDBP PICNICS PPMI
PreCEPTPostCEPT ProPark Udall
Cohort size n 440 311 580 406 317 335 150 422 120 357 321 296 252
Follow-upduration y
122 (041) 219 (151) 153 (087) 448 (145) 464 (310) 197 (000) 304 (009) 206 (170) 304 (163) 487 (135) 679 (095) 462 (114) 377 (181)
Female n () 146 (332) 121 (389) 201 (347) 148 (365) 107 (338) 110 (328) 57 (380) 174 (412) 43 (358) 121 (339) 106 (330) 105 (355) 73 (290)
Family historyn ()
86 (209) 69 (223) 148 (255) 59 (145) 43 (140) mdash 17 (113) 54 (128) 19 (158) 48 (135) 93 (292) 76 (259) 71 (284)
Age at onset y 5865 (917) 5941 (980) 6216 (1046) 6064 (945) 5433 (1006) 6079 (865) 6727 (926) 5851 (1028) 6894 (934) 6145 (955) 5947 (922) 5314 (1060) 6426 (864)
Baseline fromdiagnosis y
114 (117) 260 (157) 409 (463) 150 (100) 1013 (604) 518 (444) 013 (012) 568 (564) 023 (048) 054 (054) 080 (083) 656 (467) 621 (538)
Levodopa usen ()
0 (00) 198 (639) 415 (716) 207 (512) mdash mdash 0 (00) 255 (604) 36 (300) 0 (00) 0 (00) 202 (682) 215 (853)
Dopamineagonist use n ()
0 (00) 228 (733) 224 (386) 280 (693) mdash mdash 0 (00) 61 (145) 22 (183) 0 (00) 1 (03) 222 (750) 118 (468)
Modified HY 161 (053) 175 (055) 214 (064) mdash 219 (064) 208 (033) 186 (058) 204 (069) 164 (067) 155 (050) 175 (048) 251 (079) 229 (068)
UPDRS1 mdash 769 (450) 170 (159) 131 (145) mdash mdash 195 (176) 990 (611) mdash 540 (397) 084 (119) mdash 192 (199)
UPDRS2 mdash 772 (466) 921 (523) 729 (386) mdash mdash 819 (422) 1114 (801) mdash 580 (411) 611 (320) mdash 1074 (713)
UPDRS3 mdash 2037 (1023) 1930 (958) 1777 (832) 1542 (1030) mdash 2209 (977) 2364 (1308) mdash 2088 (900) 1869 (765) mdash 2292 (1109)
UPDRS4 mdash 066 (256) 225 (205) 134 (149) mdash mdash 057 (114) 220 (317) mdash mdash mdash mdash 202 (275)
MDS_UPDRS total mdash 3643 (1602) mdash mdash mdash mdash mdash 4688 (2404) 4727 (1797) mdash mdash mdash mdash
UPDRS total 2468 (1156) mdash 3233 (1428) 2767 (1162) mdash 3211 (1010) 3279 (1391) mdash mdash mdash 2539 (1010) mdash 3264 (1828)
MMSE 2899 (135) 2838 (173) 2835 (217) mdash mdash 2809 (161) 2788 (227) mdash 2871 (143) mdash 2929 (107) 2705 (250) 2683 (350)
MoCA mdash mdash mdash mdash mdash mdash mdash 2544 (340) mdash 2717 (223) mdash mdash 2437 (363)
SEADL 9155 (649) 8055 (2902) mdash 9159 (606) mdash mdash 8940 (735) 8511 (1310) mdash 9318 (591) 9277 (526) mdash 8053 (1756)
Hyposmia n () mdash 89 (289) mdash mdash mdash mdash 54 (360) 276 (654) mdash 164 (459) mdash 173 (638) 69 (670)
Cognitiveimpairment n ()
26 (59) 3 (10) 74 (130) 29 (71) mdash 55 (164) 27 (180) 96 (227) 11 (92) 28 (78) 3 (09) 77 (270) 29 (115)
Motorfluctuation n ()
mdash 40 (129) 228 (399) 103 (254) mdash mdash 4 (27) 129 (481) 1 (08) mdash mdash 94 (324) 75 (354)
Dyskinesia n () 4 (09) 13 (42) 207 (362) 5 (12) mdash mdash 2 (13) 196 (464) 0 (00) mdash mdash 81 (276) 44 (228)
Continued
4NeurologyG
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were dopaminergic therapy naive at baseline patients in theother cohorts were not In the primary analysis of 13 cohorts17 associations were identified as significant after FDR cor-rection (table 2 and more information in table e-4 linkslwwcomNXGA173) Overwhelmingly 10 were associated withGBA variants In particular GBA pE365K (rs2230288) wasassociated with 237- (153ndash366) (95 CI) fold higher oddsof having cognitive impairment at baseline (p = 109 times 10minus4)and 278- (188ndash411) fold higher hazard ratio (HR) of de-veloping cognitive impairment during follow-up among thosewho were negative for cognitive impairment at baseline (p =297 times 10minus7) This SNPwas also associated with a higher meanon the HY at 010 (004ndash016) (p = 153 times 10minus3) but the testof homogeneity was rejected (p= 0017 I2 = 489) In additionit was associated with the development of an RBD among thosewho did not have the disorder at baseline OtherGBAmutationspN370S (rs767763715) and pT408M (rs75548401) wereboth associated with a higher HR of reaching HY3 (459[260ndash810] for pN370S [p = 158 times 10minus7] and 193 [134ndash278]for pT408M [p = 440 times 10minus4]) GBA pN370N was also as-sociated with a higher risk of developing wearing-off dyskinesiaand daytime sleepiness pT408M was associated with a 648(204ndash2060) times higher odds ratio (OR) of having an RBDsymptom at baseline (p = 153 times 10minus3)
Two LRRK2 variants in our 31 SNPs of interest were signifi-cantly associated with outcomes LRRK2 pG2019S(rs34637584) was associated with higher odds of having a familyhistory of Parkinson disease (OR 354 [172ndash729] p = 606 times10minus4) and the T allele of rs76904798 (intergenic at the 59 end ofLRRK2) was associated with a higher HR of reaching HY3 (HR133 [116ndash152] for the T allele p = 527 times 10minus5)
Age at onset was inversely associated with theZ value of the GRS(minus060 [minus089 to minus031] years per +1 SD p = 533 times 10minus5)Moreover it was associated with rs34311866 (TMEM175pM393T) theC allele of rs199347 (intronic region ofGPNMB)and the G allele of rs1106180 (intronic region of CCDC62)
The majority (1417) of associations showed good accordacross cohorts (I2 lt 50) and the forest plots (figures 1ndash3) alsoillustrate this qualitatively Furthermore up to 13 iterations of theleave-one-out analysis assessed 15 associations of which out-comes were measured in more than 2 cohorts and showeda small range of betas Themaximum p value of 13 iterations wasless than 005 for all associations except for rs114138769 (intronof PMVK) and rs76763715 (GBA pN370S) for wearing-off Ameta-analysis with a random effect model also detected 9 asso-ciations after the same FDR correction although the model ismore conservative than a fixed model
DiscussionWe conducted a meta-analysis with 13 longitudinal patientcohorts and identified multiple associations between geno-types and clinical phenotypic characteristics includingTa
ble
1Su
mmarych
arac
teristicsof13
cohorts(con
tinue
d)
DATA
TOP
DIG
PD
HBS
NET
-PD
LS1
Oslo
Park
Fit
Park
West
PDBP
PICNICS
PPMI
Pre
CEP
TPostCEP
TPro
Park
Udall
Depre
ssionn
()
12(27)
97(316)
35(109)
40(99)
mdashmdash
20(133)
49(116)
27(225)
113(317)
73(227)
48(163)
63(250)
RLS
n(
)mdash
44(145)
37(109)
mdashmdash
mdashmdash
91(233)
mdash23
(64)
mdashmdash
mdash
Con
stipationn
()
9(20)
62(203)
mdashmdash
mdashmdash
17(113)
239(566)
29(242)
113(317)
mdash13
8(466)
mdash
RBDn
()
mdashmdash
mdashmdash
mdashmdash
mdash19
7(505)
mdash93
(261)
mdashmdash
mdash
Daytim
esleepinessn
()
5(11)
138(448)
mdashmdash
mdashmdash
25(167)
165(391)
25(208)
55(154)
mdash12
6(426)
mdash
Inso
mnian
()
11(25)
107(351)
202(351)
mdashmdash
mdash45
(300)
295(699)
62(517)
78(218)
mdash83
(280)
mdash
HYge30
n(
)0(00)
4(13)
71(124)
12(30)
22(145)
17(51)
11(73)
71(168)
13(108)
1(03)
0(00)
117(408)
57(230)
AbbreviationsDATA
TOP=Dep
renyl
andTo
copher
olA
ntioxidativeTh
erap
yofParkinso
nismD
IGPD=Dru
gInteractionwithGen
esin
Par
kinso
nrsquosDisea
seH
BS=Har
vard
Biomarke
rsStudy
HY=Hoeh
nan
dYa
hrscale
MDS=Move
men
tDisord
erSo
cietyMMSE
=Mini-Men
talS
tate
ExaminationM
oCA=Montrea
lCogn
itiveAsses
smentNET-PDLS
=NIH
Exploratory
Trialsin
Parkinso
nrsquosDisea
seLa
rgeSimple
Study1
Oslo=OsloPDstudy
ParkFit=ParkFitstudy
ParkWes
t=theNorw
egianParkWes
tstudy
PDBP=Par
kinso
nrsquosDisea
seBiomarker
Pro
gram
PICNICS=Parkinso
nismInciden
cean
dCogn
itivean
dNon-m
otorhetero
geneity
InCam
bridge
Shire
PPMI=
Parkinso
nrsquosPro
gres
sionMarke
rsInitiative
Pro
Park=Pro
filin
gParkinso
nrsquosDisea
sestudy
RBD=REM
slee
pbeh
aviordisord
erR
LS=restless
legs
syndro
me
SEADL=Sc
hwab
andEn
glan
dActivitiesofDaily
Living
Scale
UPDRS=UnifiedParkinso
nrsquosDisea
seRatingSc
ale
Continuousva
riab
lesweresu
mmarized
asmea
n(SD)
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 5
Table 2 Meta-analysis for 13 cohorts and the results of sensitivity analysis
Outcome rsNo
Known geneor nearestgene
No ofcohorts
Scale of theeffect
Fixed effect model
Test ofhomogeneity I2 ()
Leave-one-out analysis Random effect model
Estimate (95 CI) pEstimate (Min toMax) Max p Estimate (95 CI) p
Wearing-off rs114138760 intron_PMVK 9 Multiplicative (HR) 166 (119 to 231) 262E-03 0322 1258 166 (144 to 181) 622E-02 165 (114 to 238) 739E-03
Dyskinesia rs76763715 GBAN370S 8 Multiplicative (HR) 301 (181 to 501) 217E-05 0011 6053 300 (198 to 405) 226E-02 249 (106 to 586) 373E-02
HY ge 30 rs76763715 GBAN370S 6 Multiplicative (HR) 459 (260 to 810) 158E-07 0654 000 459 (402 to 541) 200E-05 459 (260 to 810) 158E-07a
Wearing-off rs76763715 GBAN370S 6 Multiplicative (HR) 203 (128 to 321) 256E-03 0021 6270 202 (161 to 265) 867E-02 192 (085 to 433) 114E-01
Daytimesleepiness
rs76763715 GBAN370S 6 Multiplicative (HR) 328 (169 to 634) 424E-04 0467 000 330 (285 to 438) 375E-03 328 (169 to 634) 424E-04a
HY ge 30 rs75548401 GBAT408M 8 Multiplicative (HR) 193 (134 to 278) 440E-04 0208 3243 193 (170 to 241) 108E-02 196 (122 to 314) 522E-03
pRBD (baseline) rs75548401 GBAT408M 2 Multiplicative (OR) 648 (204 to 2060) 153E-03 0118 5906 mdash mdash 625 (102 to 3820) 472E-02
HY rs2230288 GBAE365K 12 Continuous 010 (004 to 016) 153E-03 0017 4890 010 (008 to 011) 102E-02 011 (002 to 021) 188E-02
Cognitiveimpairment(baseline)
rs2230288 GBAE365K 8 Multiplicative (OR) 237 (153 to 366) 109E-04 0794 000 237 (220 to 259) 857E-04 237 (153 to 366) 109E-04a
Cognitiveimpairment
rs2230288 GBAE365K 9 Multiplicative (HR) 278 (188 to 411) 297E-07 0555 000 278 (241 to 298) 508E-05 278 (188 to 411) 297E-07a
pRBD rs2230288 GBAE365K 2 Multiplicative (HR) 257 (143 to 463) 169E-03 0665 000 mdash mdash 257 (143 to 463) 169E-03a
Age at onset rs34311866 TMEM175M393T
13 Continuous minus072 (minus121 to minus023) 387E-03 0515 000 minus072 (minus083 to minus058) 283E-02 minus072 (minus121 to minus023)
Age at onset rs199347 intron_GPNMB 12 Continuous 070 (027 to 114) 142E-03 0824 000 070 (060 to 077) 112E-02 070 (027 to 114) 142E-03a
HY ge 30 rs76904798 5_LRRK2 13 Multiplicative (HR) 133 (116 to 152) 527E-05 0049 4315 133 (126 to 143) 164E-03 134 (111 to 163) 280E-03a
Family history rs34637584 LRRK2G2019S 8 Multiplicative (OR) 354 (172 to 729) 606E-04 0856 000 353 (278 to 398) 166E-02 354 (172 to 729) 606E-04a
Age at onset rs11060180 intron_CCDC62 13 Continuous 062 (021 to 103) 332E-03 0054 4260 062 (049 to 075) 274E-02 055 (minus000 to 111) 514E-02
Age at onset GRS 13 Continuous minus060 (minus089 minus031) 533E-05 0749 000 minus060 (minus065 minus052) 902E-04 minus060 (minus089 minus031) 533E-05a
Abbreviations FDR = false discovery rate GRS = genetic risk score HR = hazard ratio HY = Hoehn and Yahr scale OR = odds ratio pRBD = possible REM sleep behavior disorderpRBD was only available in 2 cohorts and a leave-one-out analysis was not conducted for this outcomea Significant after FDR adjustment in a random effect model
6NeurologyG
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progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
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Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
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reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
were dopaminergic therapy naive at baseline patients in theother cohorts were not In the primary analysis of 13 cohorts17 associations were identified as significant after FDR cor-rection (table 2 and more information in table e-4 linkslwwcomNXGA173) Overwhelmingly 10 were associated withGBA variants In particular GBA pE365K (rs2230288) wasassociated with 237- (153ndash366) (95 CI) fold higher oddsof having cognitive impairment at baseline (p = 109 times 10minus4)and 278- (188ndash411) fold higher hazard ratio (HR) of de-veloping cognitive impairment during follow-up among thosewho were negative for cognitive impairment at baseline (p =297 times 10minus7) This SNPwas also associated with a higher meanon the HY at 010 (004ndash016) (p = 153 times 10minus3) but the testof homogeneity was rejected (p= 0017 I2 = 489) In additionit was associated with the development of an RBD among thosewho did not have the disorder at baseline OtherGBAmutationspN370S (rs767763715) and pT408M (rs75548401) wereboth associated with a higher HR of reaching HY3 (459[260ndash810] for pN370S [p = 158 times 10minus7] and 193 [134ndash278]for pT408M [p = 440 times 10minus4]) GBA pN370N was also as-sociated with a higher risk of developing wearing-off dyskinesiaand daytime sleepiness pT408M was associated with a 648(204ndash2060) times higher odds ratio (OR) of having an RBDsymptom at baseline (p = 153 times 10minus3)
Two LRRK2 variants in our 31 SNPs of interest were signifi-cantly associated with outcomes LRRK2 pG2019S(rs34637584) was associated with higher odds of having a familyhistory of Parkinson disease (OR 354 [172ndash729] p = 606 times10minus4) and the T allele of rs76904798 (intergenic at the 59 end ofLRRK2) was associated with a higher HR of reaching HY3 (HR133 [116ndash152] for the T allele p = 527 times 10minus5)
Age at onset was inversely associated with theZ value of the GRS(minus060 [minus089 to minus031] years per +1 SD p = 533 times 10minus5)Moreover it was associated with rs34311866 (TMEM175pM393T) theC allele of rs199347 (intronic region ofGPNMB)and the G allele of rs1106180 (intronic region of CCDC62)
The majority (1417) of associations showed good accordacross cohorts (I2 lt 50) and the forest plots (figures 1ndash3) alsoillustrate this qualitatively Furthermore up to 13 iterations of theleave-one-out analysis assessed 15 associations of which out-comes were measured in more than 2 cohorts and showeda small range of betas Themaximum p value of 13 iterations wasless than 005 for all associations except for rs114138769 (intronof PMVK) and rs76763715 (GBA pN370S) for wearing-off Ameta-analysis with a random effect model also detected 9 asso-ciations after the same FDR correction although the model ismore conservative than a fixed model
DiscussionWe conducted a meta-analysis with 13 longitudinal patientcohorts and identified multiple associations between geno-types and clinical phenotypic characteristics includingTa
ble
1Su
mmarych
arac
teristicsof13
cohorts(con
tinue
d)
DATA
TOP
DIG
PD
HBS
NET
-PD
LS1
Oslo
Park
Fit
Park
West
PDBP
PICNICS
PPMI
Pre
CEP
TPostCEP
TPro
Park
Udall
Depre
ssionn
()
12(27)
97(316)
35(109)
40(99)
mdashmdash
20(133)
49(116)
27(225)
113(317)
73(227)
48(163)
63(250)
RLS
n(
)mdash
44(145)
37(109)
mdashmdash
mdashmdash
91(233)
mdash23
(64)
mdashmdash
mdash
Con
stipationn
()
9(20)
62(203)
mdashmdash
mdashmdash
17(113)
239(566)
29(242)
113(317)
mdash13
8(466)
mdash
RBDn
()
mdashmdash
mdashmdash
mdashmdash
mdash19
7(505)
mdash93
(261)
mdashmdash
mdash
Daytim
esleepinessn
()
5(11)
138(448)
mdashmdash
mdashmdash
25(167)
165(391)
25(208)
55(154)
mdash12
6(426)
mdash
Inso
mnian
()
11(25)
107(351)
202(351)
mdashmdash
mdash45
(300)
295(699)
62(517)
78(218)
mdash83
(280)
mdash
HYge30
n(
)0(00)
4(13)
71(124)
12(30)
22(145)
17(51)
11(73)
71(168)
13(108)
1(03)
0(00)
117(408)
57(230)
AbbreviationsDATA
TOP=Dep
renyl
andTo
copher
olA
ntioxidativeTh
erap
yofParkinso
nismD
IGPD=Dru
gInteractionwithGen
esin
Par
kinso
nrsquosDisea
seH
BS=Har
vard
Biomarke
rsStudy
HY=Hoeh
nan
dYa
hrscale
MDS=Move
men
tDisord
erSo
cietyMMSE
=Mini-Men
talS
tate
ExaminationM
oCA=Montrea
lCogn
itiveAsses
smentNET-PDLS
=NIH
Exploratory
Trialsin
Parkinso
nrsquosDisea
seLa
rgeSimple
Study1
Oslo=OsloPDstudy
ParkFit=ParkFitstudy
ParkWes
t=theNorw
egianParkWes
tstudy
PDBP=Par
kinso
nrsquosDisea
seBiomarker
Pro
gram
PICNICS=Parkinso
nismInciden
cean
dCogn
itivean
dNon-m
otorhetero
geneity
InCam
bridge
Shire
PPMI=
Parkinso
nrsquosPro
gres
sionMarke
rsInitiative
Pro
Park=Pro
filin
gParkinso
nrsquosDisea
sestudy
RBD=REM
slee
pbeh
aviordisord
erR
LS=restless
legs
syndro
me
SEADL=Sc
hwab
andEn
glan
dActivitiesofDaily
Living
Scale
UPDRS=UnifiedParkinso
nrsquosDisea
seRatingSc
ale
Continuousva
riab
lesweresu
mmarized
asmea
n(SD)
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 5
Table 2 Meta-analysis for 13 cohorts and the results of sensitivity analysis
Outcome rsNo
Known geneor nearestgene
No ofcohorts
Scale of theeffect
Fixed effect model
Test ofhomogeneity I2 ()
Leave-one-out analysis Random effect model
Estimate (95 CI) pEstimate (Min toMax) Max p Estimate (95 CI) p
Wearing-off rs114138760 intron_PMVK 9 Multiplicative (HR) 166 (119 to 231) 262E-03 0322 1258 166 (144 to 181) 622E-02 165 (114 to 238) 739E-03
Dyskinesia rs76763715 GBAN370S 8 Multiplicative (HR) 301 (181 to 501) 217E-05 0011 6053 300 (198 to 405) 226E-02 249 (106 to 586) 373E-02
HY ge 30 rs76763715 GBAN370S 6 Multiplicative (HR) 459 (260 to 810) 158E-07 0654 000 459 (402 to 541) 200E-05 459 (260 to 810) 158E-07a
Wearing-off rs76763715 GBAN370S 6 Multiplicative (HR) 203 (128 to 321) 256E-03 0021 6270 202 (161 to 265) 867E-02 192 (085 to 433) 114E-01
Daytimesleepiness
rs76763715 GBAN370S 6 Multiplicative (HR) 328 (169 to 634) 424E-04 0467 000 330 (285 to 438) 375E-03 328 (169 to 634) 424E-04a
HY ge 30 rs75548401 GBAT408M 8 Multiplicative (HR) 193 (134 to 278) 440E-04 0208 3243 193 (170 to 241) 108E-02 196 (122 to 314) 522E-03
pRBD (baseline) rs75548401 GBAT408M 2 Multiplicative (OR) 648 (204 to 2060) 153E-03 0118 5906 mdash mdash 625 (102 to 3820) 472E-02
HY rs2230288 GBAE365K 12 Continuous 010 (004 to 016) 153E-03 0017 4890 010 (008 to 011) 102E-02 011 (002 to 021) 188E-02
Cognitiveimpairment(baseline)
rs2230288 GBAE365K 8 Multiplicative (OR) 237 (153 to 366) 109E-04 0794 000 237 (220 to 259) 857E-04 237 (153 to 366) 109E-04a
Cognitiveimpairment
rs2230288 GBAE365K 9 Multiplicative (HR) 278 (188 to 411) 297E-07 0555 000 278 (241 to 298) 508E-05 278 (188 to 411) 297E-07a
pRBD rs2230288 GBAE365K 2 Multiplicative (HR) 257 (143 to 463) 169E-03 0665 000 mdash mdash 257 (143 to 463) 169E-03a
Age at onset rs34311866 TMEM175M393T
13 Continuous minus072 (minus121 to minus023) 387E-03 0515 000 minus072 (minus083 to minus058) 283E-02 minus072 (minus121 to minus023)
Age at onset rs199347 intron_GPNMB 12 Continuous 070 (027 to 114) 142E-03 0824 000 070 (060 to 077) 112E-02 070 (027 to 114) 142E-03a
HY ge 30 rs76904798 5_LRRK2 13 Multiplicative (HR) 133 (116 to 152) 527E-05 0049 4315 133 (126 to 143) 164E-03 134 (111 to 163) 280E-03a
Family history rs34637584 LRRK2G2019S 8 Multiplicative (OR) 354 (172 to 729) 606E-04 0856 000 353 (278 to 398) 166E-02 354 (172 to 729) 606E-04a
Age at onset rs11060180 intron_CCDC62 13 Continuous 062 (021 to 103) 332E-03 0054 4260 062 (049 to 075) 274E-02 055 (minus000 to 111) 514E-02
Age at onset GRS 13 Continuous minus060 (minus089 minus031) 533E-05 0749 000 minus060 (minus065 minus052) 902E-04 minus060 (minus089 minus031) 533E-05a
Abbreviations FDR = false discovery rate GRS = genetic risk score HR = hazard ratio HY = Hoehn and Yahr scale OR = odds ratio pRBD = possible REM sleep behavior disorderpRBD was only available in 2 cohorts and a leave-one-out analysis was not conducted for this outcomea Significant after FDR adjustment in a random effect model
6NeurologyG
enetics
|Vo
lume5N
umber
4|
Augu
st2019
NeurologyorgN
G
progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
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httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
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nextAn erratum has been published regarding this article Please see
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httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
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reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Table 2 Meta-analysis for 13 cohorts and the results of sensitivity analysis
Outcome rsNo
Known geneor nearestgene
No ofcohorts
Scale of theeffect
Fixed effect model
Test ofhomogeneity I2 ()
Leave-one-out analysis Random effect model
Estimate (95 CI) pEstimate (Min toMax) Max p Estimate (95 CI) p
Wearing-off rs114138760 intron_PMVK 9 Multiplicative (HR) 166 (119 to 231) 262E-03 0322 1258 166 (144 to 181) 622E-02 165 (114 to 238) 739E-03
Dyskinesia rs76763715 GBAN370S 8 Multiplicative (HR) 301 (181 to 501) 217E-05 0011 6053 300 (198 to 405) 226E-02 249 (106 to 586) 373E-02
HY ge 30 rs76763715 GBAN370S 6 Multiplicative (HR) 459 (260 to 810) 158E-07 0654 000 459 (402 to 541) 200E-05 459 (260 to 810) 158E-07a
Wearing-off rs76763715 GBAN370S 6 Multiplicative (HR) 203 (128 to 321) 256E-03 0021 6270 202 (161 to 265) 867E-02 192 (085 to 433) 114E-01
Daytimesleepiness
rs76763715 GBAN370S 6 Multiplicative (HR) 328 (169 to 634) 424E-04 0467 000 330 (285 to 438) 375E-03 328 (169 to 634) 424E-04a
HY ge 30 rs75548401 GBAT408M 8 Multiplicative (HR) 193 (134 to 278) 440E-04 0208 3243 193 (170 to 241) 108E-02 196 (122 to 314) 522E-03
pRBD (baseline) rs75548401 GBAT408M 2 Multiplicative (OR) 648 (204 to 2060) 153E-03 0118 5906 mdash mdash 625 (102 to 3820) 472E-02
HY rs2230288 GBAE365K 12 Continuous 010 (004 to 016) 153E-03 0017 4890 010 (008 to 011) 102E-02 011 (002 to 021) 188E-02
Cognitiveimpairment(baseline)
rs2230288 GBAE365K 8 Multiplicative (OR) 237 (153 to 366) 109E-04 0794 000 237 (220 to 259) 857E-04 237 (153 to 366) 109E-04a
Cognitiveimpairment
rs2230288 GBAE365K 9 Multiplicative (HR) 278 (188 to 411) 297E-07 0555 000 278 (241 to 298) 508E-05 278 (188 to 411) 297E-07a
pRBD rs2230288 GBAE365K 2 Multiplicative (HR) 257 (143 to 463) 169E-03 0665 000 mdash mdash 257 (143 to 463) 169E-03a
Age at onset rs34311866 TMEM175M393T
13 Continuous minus072 (minus121 to minus023) 387E-03 0515 000 minus072 (minus083 to minus058) 283E-02 minus072 (minus121 to minus023)
Age at onset rs199347 intron_GPNMB 12 Continuous 070 (027 to 114) 142E-03 0824 000 070 (060 to 077) 112E-02 070 (027 to 114) 142E-03a
HY ge 30 rs76904798 5_LRRK2 13 Multiplicative (HR) 133 (116 to 152) 527E-05 0049 4315 133 (126 to 143) 164E-03 134 (111 to 163) 280E-03a
Family history rs34637584 LRRK2G2019S 8 Multiplicative (OR) 354 (172 to 729) 606E-04 0856 000 353 (278 to 398) 166E-02 354 (172 to 729) 606E-04a
Age at onset rs11060180 intron_CCDC62 13 Continuous 062 (021 to 103) 332E-03 0054 4260 062 (049 to 075) 274E-02 055 (minus000 to 111) 514E-02
Age at onset GRS 13 Continuous minus060 (minus089 minus031) 533E-05 0749 000 minus060 (minus065 minus052) 902E-04 minus060 (minus089 minus031) 533E-05a
Abbreviations FDR = false discovery rate GRS = genetic risk score HR = hazard ratio HY = Hoehn and Yahr scale OR = odds ratio pRBD = possible REM sleep behavior disorderpRBD was only available in 2 cohorts and a leave-one-out analysis was not conducted for this outcomea Significant after FDR adjustment in a random effect model
6NeurologyG
enetics
|Vo
lume5N
umber
4|
Augu
st2019
NeurologyorgN
G
progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
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Errata
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nextAn erratum has been published regarding this article Please see
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httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
progression rates Among these GBA coding variants showedclear associations with the rate of cognitive decline (binomialoutcome or UPDRS part 1 score) and motor symptom pro-gression (HY HY3) consistent with previous studies1221ndash25
In addition we found associations between GBA variants andRBD and daytime sleepiness A previous cross-sectional studywith 120 Ashkenazi-Jewish patients reported a higher frequencyof RBDSQ-detected RBD symptoms in GBA variant carriers26
Figure 1 Forest plots for GBA (pN370S and pT408M) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 7
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
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Errata
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nextAn erratum has been published regarding this article Please see
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httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
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httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Our finding suggests that GBA is associated not only withbaseline clinical presentation but also with disease progression
An association between GBA and daytime sleepiness has beenrarely documented One study reported an association betweensleep problems (as assessed by the Parkinsonrsquos Disease SleepScale) andGBA27 However this scale is a combined measure ofdaytime sleepiness and other aspects of sleep problems
Finally a GBA variant (pN370S) was also associated withtreatment-related complications of wearing-off and dyskine-sia Two studies have reported the association ofGBA variantswith these complications with 1 positive and 1 negativeresult2829 The negative result may be due to insufficientpower with only 19 patients with GBA mutations
Overall our study provides a distinct clinical profile ofpatients with GBA variants compared with those without We
note that with 63 carriers for pN370S 166 for pT408M and217 for pE365K we have a reasonable power but the numberis yet not enough And this may affect the results in seeminglydifferent magnitudes of associations and the association fordifferent traits per variants (eg motor complications withpN370S and cognitive impairment with pE365K) Anotherpossible explanation is that although the effects are associatedwith the same gene the biological activity or molecularmechanism could be different Such an example has alreadybeen reported for LRRK2 pG2019S and pG2385R30
Aside from GBA variants the associations between closeintergenic (59_end) variant of LRRK2 rs76904798 and thefaster development of motor symptom and the intronic re-gion variant of PMVK rs114138760 and the development ofwearing-off were significant This variant is 43 kb upstreamfrom the 59 end of LRRK2 and reported to be associated withLRRK2 gene expression changes in recent blood cis-
Figure 2 Forest plots for GBA (pE365K) variants and symptoms of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 =NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo =Oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
8 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
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httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
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Errata
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nextAn erratum has been published regarding this article Please see
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httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
expression quantitative trait loci (eQTL) study from theeQTLGen Consortium31 In contrast we did not find an as-sociation between rs34637584 LRRK2 coding mutation(pG2019S) and motor progression The pG2019 variant isa rare variant (MAF 05 in our study) and our sample sizewas not adequate barring an extremely large effect size Theintronic region variant of PMVK rs114138760 and the de-velopment of wearing-off was another finding The biologicaleffect of PMVK on PD has not been reported but the variantis also located at close proximity of theGBA-SYT11 locus so it
is possible that its association was through a similar mechanismas GBA Including the results of cross-sectional analysis theassociations of age at onset with rs34311866 (TMEM175pM393T) rs199347 (intron of GPNMB) and rs11060180(intron of CCDC62) were found TMEM175 has been repor-ted to impair lysosomal and mitochondrial function and in-crease α-synuclein aggregation32 although no functional datafor this missense variant were studied Of interest the varianthas recently been reported in another study as being associatedwith the age at onset33 rs199347 is an eQTL increasing the
Figure 3 Forest plots for non-GBA risk variantsgenetic risk score and symptoms or features of Parkinson disease
DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism DIGPD = Drug Interaction with Genes in Parkinsonrsquos Disease HBS = HarvardBiomarkers Study NET-PD_LS1 = NIH Exploratory Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo = oslo PD study ParkFit = ParkFit study ParkWest =the Norwegian ParkWest study PDBP = Parkinsonrsquos Disease Biomarker Program PICNICS = Parkinsonism Incidence and Cognitive and Non-motor het-erogeneity In CambridgeShire PPMI = Parkinsonrsquos Progression Markers Initiative PreCEPTPostCEPT = Parkinson Research Examination of CEP-1347 Trialwith a subsequent prospective study ProPark = Profiling Parkinsonrsquos Disease study Udall = Morris K Udall Centers for Parkinsonrsquos Research Indicates Betain a Cox model indicates Beta in a logistic model at baseline indicates Beta in a linear mixed model
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 9
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
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httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
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httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
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httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
brain expression of GPNMB34 suggesting a causal link Re-garding rs1160180 no functional data are available in this locus
We also evaluated the association between genetic risk var-iants and clinical outcomes by 2-step meta-analysis Thisanalysis is exploratory and we acknowledge that this is biasedtoward the null due to power issues when partitioning studiesrandomly However we believe that it is helpful to assess therigorousness of the associations we found in the primaryanalysis and to explore potential missed associations
A strength of the current study was its design incorporatingmultiple distinct independent Parkinson disease cohorts withlongitudinal follow-ups Although the cohorts containedpatients at different disease stages and some of the definitionof outcomes were not identical we analyzed each cohortseparately and combined the results Thus the significantfindings are consistent and applicable to the wider Parkinsondisease populations The forest plots showed that most of theestimates agree with each other despite the relative differencesin the cohort characteristics Another strength is the size of thestudy The total number of genotyped and phenotypedpatients with Parkinson disease (N = 4307) is one of thelargest to date for an investigation of disease progression
The limitations of our study were as follows First we onlyincluded patients of European ancestry It is uncertain whetherthe associations in the current study are also applicable to peoplefrom different ethnic backgrounds and further research isneeded Second the current analysis could not distinguish cau-sality only basic associations Different approaches such asmolecular-level assessment and Mendelian randomization arecrucial Third interaction effects between genes and other factorsare another important research target not addressed in this re-port because of power constraints For example gene-by-smoking interactions for Parkinson disease were indicated re-cently35 and highlight the importance of correctly modelinggene-environment interactions Finally compared with the typ-ical GWAS analysis (which includes tens of thousands of cases)the number of participants was small and the outcomes of in-terest were not as simple or easily defined as with case-controldistinctions in GWAS Acknowledging the limitations the list ofassociations provided here is valuable as a foundation for furtherstudies and as an example that illustrates the potential of effortsto define the genetic basis of variability in presentation andcourse Accounting for this variability even in part has the po-tential to positively affect etiology-based clinical trials by re-ducing variability between placebo and treatment groups and byproviding better predictions of expected individual progression
AcknowledgmentThe authors thank all study participants and their familyinvestigators and members of the following studies ParkinsonStudy Group Deprenyl and Tocopherol AntioxidativeTherapy of Parkinsonism (DATATOP) Drug Interactionwith Genes in Parkinsonrsquos Disease (DIGPD) HarvardBiomarkers Study (HBS) NET-PD_LS1 NIH Exploratory
Trials in Parkinsonrsquos Disease Large Simple Study 1 Oslo PDstudy ParkFit study The Norwegian ParkWest study(ParkWest) Parkinsonrsquos Disease Biomarker Program (PDBP)Parkinsonism Incidence and Cognitive and Non-motorheterogeneity In CambridgeShire (PICNICS) Parkinsonrsquosprogression markers initiative (PPMI) Parkinson StudyGroup Parkinson Research Examination of CEP-1347 Trial(PreCEPT) and its following study (PostCEPT) ProfilingParkinsonrsquos disease study (ProPark) and Morris K UdallCenters for Parkinsonrsquos Research (Udall) They also thank thefollowing grants and financial supporters of above studiesDATATOP was supported by a Public Health Service grant(NS24778) from the NINDS by grants from the GeneralClinical Research Centers Program of the NIH at ColumbiaUniversity (RR00645) the University of Virginia (RR00847)the University of Pennsylvania (RR00040) the University ofIowa (RR00059) Ohio State University (RR00034) Massa-chusetts General Hospital (RR01066) the University ofRochester (RR00044) Brown University (RR02038) OregonHealth Sciences University (RR00334) Baylor College ofMedicine (RR00350) the University of California (RR00827)Johns Hopkins University (RR00035) the University ofMichigan (RR00042) and Washington University(RR00036) the Parkinsonrsquos Disease Foundation atColumbia-Presbyterian Medical Center the National Parkin-son Foundation the Parkinson Foundation of Canada theUnited Parkinson Foundation Chicago the American Parkin-sonrsquos Disease Association New York and the University ofRochester DIGPD is supported by Assistance PubliqueHopitaux de Paris funded by a grant from the French Ministryof Health (PHRC 2008 AOM08010) and a grant from theAgence Nationale pour la Securite des Medicaments (ANSM2013) HBS is supported by the Harvard NeuroDiscoveryCenter Michael J Fox Foundation NINDS U01NS082157U01NS100603 and the Massachusetts Alzheimerrsquos DiseaseResearch Center NIA P50AG005134 NET-PD_LS1 wassupported by NINDS grants U01NS043128 OSLO issupported by the Research Council of Norway and South-Eastern Norway Regional Health Authority ParkFit issupported by ZonMw (the Netherlands Organization forHealth Research and Development [75020012]) and theMichael J Fox Foundation for Parkinsonrsquos research VGZ(health insurance company) GlaxoSmithKline and theNational Parkinson Foundation ParkWest is supported bythe Research Council of Norway the Western NorwayRegional Health Authority Stavanger University HospitalResearch Funds and the Norwegian Parkinsonrsquos DiseaseAssociation PDBP is a consortium with NINDS initiativePICNICS has received funding from the Cure ParkinsonrsquosTrust the Van Geest Foundation and is supported by the NIHResearch Cambridge Biomedical Research Centre PPMI issupported by the Michael J Fox Foundation for Parkinsonrsquosresearch PreCEPT and PostCEPT were funded by NINDS5U01NS050095-05 Department of Defense NeurotoxinExposure Treatment Parkinsonrsquos Research Program (GrantNumber W23RRYX7022N606) the Michael J Fox Founda-tion for Parkinsonrsquos Research Parkinsonrsquos Disease Foundation
10 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Lundbeck Pharmaceuticals Cephalon Inc Lundbeck Inc JohnBlume Foundation Smart Family Foundation RJG Founda-tion Kinetics Foundation National Parkinson FoundationAmarin Neuroscience LTD CHDI Foundation Inc NIH(NHGRI and NINDS) and Columbia Parkinsonrsquos DiseaseResearch Center ProPARK is funded by the Alkemade-KeulsFoundation Stichting Parkinson Fonds Parkinson Verenigingand The Netherlands Organization for Health Research andDevelopment Udall is supported by the NINDS
Study fundingThis study is supported by the Intramural Research Programthe National Institute on Aging (NIA Z01-AG000949-02)Biogen Idec and the Michael J Fox Foundation for Parkin-sonrsquos Research The funders of the study had no role in studydesign data collection data analysis data interpretation orwriting of the report The authors had full access to the data inthe study and had final responsibility for the decision tosubmit for publication
DisclosureH Iwakimdashgrants Michael J Fox Foundation J Maple-Groslashdemmdashgrants Norwegian Parkinsonrsquos Disease Associa-tion J-C Corvolmdashadvisory boards Biogen Air LiquideBrainEver Theranexus BMS Zambon Pfizer Ipsen andAbbVie grants MJFF Actelion and Ipsen L Pihlstroslashmmdashgrants Norwegian Health Association South-East NorwayRegional Health Authority Norwegian Parkinson ResearchFund and Michael J Fox Foundation K-DH Nguyenmdashstock ownership in medically related fields BiotechPharmaceutical Industry KM Scottmdashgrants WellcomeTrust PhD Fellowship VM Van Deerlinmdashgrants NIH NS-053488 AG Day-Williamsmdashstock ownership in medicallyrelated fields Biogen and Merck A Bricemdashadvisory boardsFWO and ERC grants JPND ANR Eranet Neuron andAssociation France Parkinson AJ Noycemdashhonoraria Bri-tannia Pharmaceuticals grants Parkinsonrsquos UK (G-1606)JR Evansmdashadvisory boards AbbVie Global Kinetics andAllergan honoraria UCB Allergan and AbbVie KEstradamdashstock ownership in medically related fields BiogenDK Simonmdashconsultancies Lysosomal Therapeutics Incadvisory boards Weston Brain Institute honoraria Parkin-son Study Group Harvard Medical School Michael J FoxFoundation and Biogen grants NIH Weston Brain In-stitute Mission Therapeutics Inc and BioElectron Tech-nologies B Ravinamdashstock ownership in medically relatedfields Voyager Therapeutics consultancies Michael J FoxFoundation M Toftmdashhonoraria Roche grants ResearchCouncil of Norway South-Eastern Norway Regional HealthAuthority and Michael J Fox Foundation BR Bloemmdashconsultancies AbbVie and Zambon advisory boards MichaelJ Fox Foundation honoraria and speaker fees AbbVieZambon and Bial grants The Netherlands Organization forScientific Research the Michael J Fox Foundation UCBAbbVie the Stichting Parkinson Fonds the HersenstichtingNederland the Parkinsonrsquos Foundation Verily Life Sciencesthe Topsector Life Sciences and Health and the Parkinson
Vereniging D Weintraubmdashconsultancies Acadia AlkahestAnavex Life Sciences BlackThorn Therapeutics BracketClintrex LLC Sunovion Theravance Biopharma and theCHDI Foundation RA Barkermdashconsultancies CDI andOxford Biomedica royalties Springer and Wiley grants EUNIHR PUK CPT Rosetrees Trust MRC Wellcome Trustand Evelyn Trust CH Williams-Graymdashgrants MRC Clini-cian Scientist fellowship the NIHR Cambridge BiomedicalResearch Centre the Michael J Fox Foundation the Rosetr-ees Trust the Evelyn Trust and Addenbrookes CharitableTrust BP van de Warrenburgmdashadvisory boards member ofmedical advisory boards and patient organizations royaltiesReed Elsevier (for chapter in Dutch Neurology textbook)grants Radboud University Medical Centre ZonMW Her-senstichting and Bioblast Pharma JJ Van HiltenmdashgrantsAlkemade-Keuls Foundation Stichting Parkinson FondsParkinson Vereniging and The Netherlands Organisation forHealth Research and Development CR ScherzermdashgrantsNIH grants U01NS082157 U01NS095736 andU01NS100603MA Nallsmdashconsultancies Lysosomal Therapies Inc VividGenomics Inc Kleiner Perkins Caufield amp Byers and Michael JFox Foundation Go to NeurologyorgNG for full disclosures
Publication historyReceived by Neurology Genetics November 13 2018 Accepted in finalform April 30 2019
Appendix Authors
Name Location Role Contributions
Hirotaka IwakiMD PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchstudy design dataanalysis datainterpretation andwritings
CornelisBlauwendraatPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Literature searchdata analysis datainterpretation andcritical review
Hampton LLeonard MS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Critical review
Ganqiang LiuPhD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBoston MA
Author Data collection andcritical review
Jodi Maple-Groslashdem PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Continued
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 11
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
Appendix (continued)
Name Location Role Contributions
Jean-ChristopheCorvol MDPhD
Assistance-PubliqueHopitaux de ParisICM INSERM UMRS1127 CNRS 7225ICM Department ofNeurology and CICNeurosciences Pitie-Salpetriere HospitalParis France
Author Data collection andcritical review
LassePihlstroslashm MDPhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Marlies vanNimwegenPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Samantha JHutten PhD
Michael J FoxFoundation NewYork NY
Author Data collection andcritical review
Khanh-Dung HNguyen PhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
JacquelineRick PhD
Department ofNeurology Universityof PennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Shirley EberlyMS
Department ofBiostatistics andComputationalBiology University ofRochester RochesterNY
Author Data collection andcritical review
Faraz FaghriMS
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Peggy AuingerMS
Department ofNeurology Center forHealth + TechnologyUniversity ofRochester RochesterNY
Author Data collection andcritical review
Kirsten MScott MRCPMPhil
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
RuwaniWijeyekoonMRCP
Department ofClinicalNeurosciencesUniversity ofCambridge John vanGeest Centre forBrain RepairCambridge UK
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Vivianna MVan DeerlinMD PhD
Department ofPathology andLaboratory MedicineCenter forNeurodegenerativeDisease ResearchParelman School ofMedicine at theUniversity ofPennsylvaniaPhiladelphia PA
Author Data collection andcritical review
Dena GHernandezPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Data collection andcritical review
Aaron G Day-Williams PhD
Genetics andPharmacogenomicsMerck ResearchLaboratory BostonMA
Author Data collection andcritical review
Alexis BriceMD
Institut du cerveau etde la moelle epiniereICM Paris France
Author Data collection andcritical review
Guido AlvesMD PhD
The NorwegianCentre for MovementDisorders StavangerUniversity HospitalStavanger Norway
Author Data collection andcritical review
Alastair JNoyce MRCPPhD
Preventive NeurologyUnit WolfsonInstitute ofPreventive MedicineQueen MaryUniversity of LondonLondon UK
Author Data collection andcritical review
Ole-BjoslashrnTysnes MDPhD
Department ofNeurologyHaukeland UniversityHospital BergenNorway
Author Data collection andcritical review
Jonathan REvans MRCPPhD
Department ofNeurologyNottinghamUniversity NHS TrustNottingham UK
Author Data collection andcritical review
David P BreenMRCP PhD
Centre for ClinicalBrain SciencesUniversity ofEdinburghEdinburgh Scotland
Author Data collection andcritical review
Karol EstradaPhD
TranslationalGenome SciencesBiogen CambridgeMA
Author Data collection andcritical review
Claire E WegelMPH
Department ofMedical andMolecular GeneticsIndiana UniversityIndianapolis IN
Author Data collection andcritical review
FabriceDanjou MDPhD
Institut du cerveauet de la moelleepiniere ICM ParisFrance
Author Data collection andcritical review
12 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
References1 Elbaz A Bower JH Maraganore DM et al Risk tables for parkinsonism and Par-
kinsonrsquos disease J Clin Epidemiol 20025525ndash312 Chaudhuri KR Healy DG Schapira AHV National Institute for Clinical Excellence
Non-motor symptoms of Parkinsonrsquos disease diagnosis and management LancetNeurol 20065235ndash245
3 Lewis SJG Foltynie T Blackwell AD Robbins TW Owen AM Barker RA Het-erogeneity of Parkinsonrsquos disease in the early clinical stages using a data drivenapproach J Neurol Neurosurg Psychiatry 200576343ndash348
4 Satake W Nakabayashi Y Mizuta I et al Genome-wide association study identifiescommon variants at four loci as genetic risk factors for Parkinsonrsquos disease Nat Genet2009411303ndash1307
5 Simon-Sanchez J Schulte C Bras JM et al Genome-wide association study revealsgenetic risk underlying Parkinsonrsquos disease Nat Genet 2009411308ndash1312
6 Chang D Nalls MA Hallgrımsdottir IB et al A meta-analysis of genome-wide as-sociation studies identifies 17 new Parkinsonrsquos disease risk loci Nat Genet 2017491511ndash1516
7 International Parkinson Disease Genomics Consortium Nalls MA Plagnol V Her-nandez DG et al Imputation of sequence variants for identification of genetic risks forParkinsonrsquos disease a meta-analysis of genome-wide association studies Lancet 2011377641ndash649
8 Nalls MA Bras J Hernandez DG et al NeuroX a fast and efficient genotypingplatform for investigation of neurodegenerative diseases Neurobiol Aging 2015361605e7ndash1605e12
9 Nalls MA Escott-Price V Williams NM et al Genetic risk and age in Parkinsonrsquosdisease continuum not stratum Mov Disord 201530850ndash854
10 Nalls MA McLean CY Rick J et al Diagnosis of Parkinsonrsquos disease on the basis ofclinical and genetic classification a population-based modelling study Lancet Neurol2015141002ndash1009
11 Pankratz N Beecham GW DeStefano AL et al Meta-analysis of Parkinsonrsquos diseaseidentification of a novel locus RIT2 Ann Neurol 201271370ndash384
12 Davis AA Andruska KM Benitez BA Racette BA Perlmutter JS Cruchaga C Var-iants in GBA SNCA and MAPT influence Parkinson disease risk age at onset andprogression Neurobiol Aging 201637209e1ndash209e7
13 Picillo M Pellecchia MT Erro R et al The use of university of Pennsylvania Smell identi-fication test in the diagnosis of Parkinsonrsquos disease in Italy Neurol Sci 201435379ndash383
14 Hoops S Nazem S Siderowf AD et al Validity of the MoCA and MMSE in thedetection of MCI and dementia in Parkinson disease Neurology 2009731738ndash1745
15 Verbaan D van Rooden SM van Hilten JJ Rijsman RM Prevalence and clinicalprofile of restless legs syndrome in Parkinsonrsquos disease Mov Disord 2010252142ndash2147
16 Goodarzi Z Mrklas KJ Roberts DJ Jette N Pringsheim T Holroyd-Leduc JDetecting depression in Parkinson disease a systematic review and meta-analysisNeurology 201687426ndash437
17 Simuni T Caspell-Garcia C Coffey C et al Correlates of excessive daytimesleepiness in de novo Parkinsonrsquos disease a case control study Mov Disord2015301371ndash1381
18 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in an aging and dementia cohort Sleep Med201112445ndash453
19 Nomura T Inoue Y Kagimura T Uemura Y Nakashima K Utility of the REM sleepbehavior disorder screening questionnaire (RBDSQ) in Parkinsonrsquos disease patientsSleep Med 201112711ndash713
20 Boeve BF Molano JR Ferman TJ et al Validation of the Mayo sleep questionnaire toscreen for REM sleep behavior disorder in a community-based sample J Clin SleepMed 20139475ndash480
21 Davis MY Johnson CO Leverenz JB et al Association of GBA mutations and theE326K polymorphism with motor and cognitive progression in Parkinson diseaseJAMA Neurol 2016731217ndash1224
Appendix (continued)
Name Location Role Contributions
David K SimonMD PhD
Department ofNeurology BethIsrael DeaconessMedical CenterBoston MA
Author Data collection andcritical review
BernardRavina MD
VoyagerTherapeuticsCambridgeMA
Author Data collection andcritical review
Mathias ToftMD PhD
Department ofNeurology OsloUniversity HospitalOslo Norway
Author Data collection andcritical review
Peter HeutinkPhD
German Center forNeurodegenerativeDiseases-TubingenTuebingen Germany
Author Data collection andcritical review
Bastiaan RBloem MDPhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
DanielWeintraub MD
Department ofPsychiatry Universityof PennsylvaniaSchool of MedicinePhiladelphiaPA
Author Data collection andcritical review
Roger ABarker MRCPPhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Caroline HWilliams-GrayMRCP PhD
Department ofClinicalNeurosciencesUniversity ofCambridgeCambridgeUK
Author Data collection andcritical review
Bart P van deWarrenburgMD PhD
Department ofNeurology DondersInstitute for BrainCognition andBehaviour RadboudUniversity MedicalCentre NijmegenThe Netherlands
Author Data collection andcritical review
Jacobus J VanHilten MDPhD
Department ofNeurology LeidenUniversity MedicalCenter Leiden TheNetherlands
Author Data collection andcritical review
Clemens RScherzer MD
Precision NeurologyProgram HarvardMedical SchoolBrigham andWomenrsquos HospitalBostonMA
Author Data collection andcritical review
Appendix (continued)
Name Location Role Contributions
Andrew BSingleton PhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design andcritical review
Mike A NallsPhD
Laboratory ofNeurogeneticsNational Institute onAging NationalInstitutes of HealthBethesda MD
Author Study design dataanalysis datainterpretation andcritical review
NeurologyorgNG Neurology Genetics | Volume 5 Number 4 | August 2019 13
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
22 Winder-Rhodes SE Evans JR Ban M et al Glucocerebrosidase mutations influencethe natural history of Parkinsonrsquos disease in a community-based incident cohort Brain2013136392ndash399
23 Brockmann K Srulijes K Pflederer S et al GBA-associated Parkinsonrsquos diseasereduced survival and more rapid progression in a prospective longitudinal study MovDisord 201530407ndash411
24 Liu G Boot B Locascio JJ et al Specifically neuropathic Gaucherrsquos mutations ac-celerate cognitive decline in Parkinsonrsquos Ann Neurol 201680674ndash685
25 Liu G Locascio JJ Corvol JC et al Prediction of cognition in Parkinsonrsquos disease witha clinical-genetic score a longitudinal analysis of nine cohorts Lancet Neurol 201716620ndash629
26 Gan-Or Z Mirelman A Postuma RB et al GBA mutations are associated with rapideye movement sleep behavior disorder Ann Clin Transl Neurol 20152941ndash945
27 Brockmann K Srulijes K Hauser AK et al GBA-associated PD presents with non-motor characteristics Neurology 201177276ndash280
28 Oeda T Umemura A Mori Y et al Impact of glucocerebrosidase mutations on motorand nonmotor complications in Parkinsonrsquos disease Neurobiol Aging 2015363306ndash3313
29 Jesus S Huertas I Bernal-Bernal I et al GBA variants influence motor and non-motorfeatures of Parkinsonrsquos disease PLoS One 201611e0167749
30 Marras C Alcalay RN Caspell-Garcia C et al Motor and nonmotor heteroge-neity of LRRK2-related and idiopathic Parkinsonrsquos disease Mov Disord 2016311192ndash1202
31 Votildesa U Claringbould P Westra HJ et al Unraveling the polygenic architecture ofcomplex traits using blood eQTL meta-analysis bioRxiv Epub 2018 Oct 19
32 Jinn S Drolet RE Cramer PE et al TMEM175 deficiency impairs lysosomal andmitochondrial function and increases α-synuclein aggregation Proc Natl Acad Sci U SA 20171142389ndash2394
33 Blauwendraat C Heilbron K Vallerga CL Bandres-Ciga S Coelln Rvon Pihlstroslashm LParkinson disease age at onset GWAS defining heritability genetic loci and α-syn-uclein mechanisms Mov Disord Epub 2019 Apr 7
34 UKBEC Murthy MN Blauwendraat C Guelfi S et al Increased brain expression ofGPNMB is associated with genome wide significant risk for Parkinsonrsquos disease onchromosome 7p153 Neurogenetics 201718121ndash133
35 Lee PC Ahmed I Loriot MA et al Smoking and Parkinson disease evidence forgene-by-smoking interactions Neurology 201890e583ndashe592
14 Neurology Genetics | Volume 5 Number 4 | August 2019 NeurologyorgNG
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
DOI 101212NXG000000000000034820195 Neurol Genet
Hirotaka Iwaki Cornelis Blauwendraat Hampton L Leonard et al cohorts
Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal
This information is current as of July 9 2019
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
ServicesUpdated Information amp
httpngneurologyorgcontent54e348fullhtmlincluding high resolution figures can be found at
References httpngneurologyorgcontent54e348fullhtmlref-list-1
This article cites 33 articles 2 of which you can access for free at
Citations httpngneurologyorgcontent54e348fullhtmlotherarticles
This article has been cited by 7 HighWire-hosted articles
Subspecialty Collections
httpngneurologyorgcgicollectionprognosisPrognosis
mhttpngneurologyorgcgicollectionparkinsons_disease_parkinsonisParkinsons diseaseParkinsonism
ntiahttpngneurologyorgcgicollectionparkinsons_disease_with_demeParkinsons disease with dementia
httpngneurologyorgcgicollectioncohort_studiesCohort studies
httpngneurologyorgcgicollectionassociation_studies_in_geneticsAssociation studies in geneticsfollowing collection(s) This article along with others on similar topics appears in the
Errata
content54e354fullpdf or page
nextAn erratum has been published regarding this article Please see
Permissions amp Licensing
httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2019 The Author(s)
is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
CORRECTION
Genetic risk of Parkinson disease and progression An analysis of 13longitudinal cohortsNeurol Genet 20195e354 doi101212NXG0000000000000354
In the article ldquoGenetic risk of Parkinson disease and progression An analysis of 13 longitudinalcohorts by Iwaki et al1 first published online July 9 2019 in the abstractrsquos results the phraseshould be ldquoT allele of rs114128760rdquo The authors regret the error
Reference1 Iwaki H Blauwendraat C Leonard HL et al Genetic risk of Parkinson disease and progression An analysis of 13 longitudinal cohorts
Neurol Genet 20195e348
Copyright copy 2019 American Academy of Neurology 1
Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited
