July 11, 2010 Honolulu - University of...
Transcript of July 11, 2010 Honolulu - University of...
Alzheimer Disease Genetics
Consortium: Organization & Progress
Lindsay A. Farrer
Genetics Program
Boston University School of
Medicine
International Conference on Alzheimer Disease
July 11, 2010 Honolulu
• Identify genetic variants that cause AD
• Identify genetic variants that increase risk for AD
• Identify genetic variants that affect AD endophenotypes(Aβ load, tangle load, psychosis, biomarker levels, etc.)
Goals
• Identify genetic variants that cause AD
• Identify genetic variants that increase risk for AD
• Identify genetic variants that affect AD endophenotypes(Aβ load, tangle load, psychosis, biomarker levels, etc.)
Bring together AD investigators, datasets, and resources for large genome wide
association studies of AD and related traits
Solve the genetics of Alzheimer disease
Goals
• Acquire and assemble existing GWAS datasets
• Acquire and genotype de novo samples from ADCs and population-based studies using high-density SNP platforms
• Analyze all GWAS datasets using a variety of approaches
• Assemble and analyze data from a replication cohort
Mechanism
July 2007: small NIA-organized planning meeting
August 2007: large comprehensive NIA-organized meetingADGC is formed
November 2007: NIA funds NACC/NCRAD for initial sample collection
April 2008: Private foundation funds initial ADGC analyses using existing GWAS datasets
April 2009: UO1 is funded
August 2009: initial genotyping completed (2,100 subjects)
History of the ADGC
ADGC Projects – year one/two
1. Analysis of existing GWAS datasets
2. Genotyping and analysis of ADC autopsy cases/controls
3. Genotyping and analysis of ADC Uniform dataset (UDS) clinical cases/controls
4. AD GWAS including all available datasets
5. GWAS of CSF biomarker traits
Washington University: 431University of Washington: > 500
ADNI: 491*University of Pennsylvania: 283
* Not funded by the ADGC but data is/will be available
6. GWAS analysis of prospective cohorts (European Ancestry)
ADGC Projects – years two thru five
incident incidentCohort PI n > 3 evals. dementia MCI
CHAP Evans 2,300 1,500 210 270
WHICAP Mayeux 904 586 59 105
MAP Bennett 1,050 950 150 250
WHISCA Resnick 2,275 2,000 85 170
ACT* Larson 2,100 ~300
ADPR* Kukull ~300
* Not funded by the ADGC but data is/will be available
Administration – UPenn teamExternal Advisory
CommitteeInvestigator Committee
ADGC Organization
Executive Committee
Administration – UPenn team
Familial AD Committee
Prospective Cohort
Committee
External Advisory
Committee
Analysis Committee
Neuropath. Committee
Biomarker Committee
Investigator Committee
Clinical Committee
ADGC Organization
Executive Committee
29 ADCs
Bud Kukulldata
cleaning
Alzheimer’s Disease Center Samples
NACC
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
Selection of samples for GWASNACC
ADGC
Bud Kukull
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
Selection of samples for GWAS
Autopsy SamplesNeuropathology committee
• Thomas Montine: chair, co-PI• Eric Reiman: co-PI• Dennis Dickson• Matthew Frosch• Bernadino Ghetti• Brad Hyman• Julie Schneider• John Trojanowski
• Walter Kukull NACC• Gerard Schellenberg ADGC
NACC
ADGC
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
Selection of samples for GWAS
subject lists
Autopsy SamplesNeuropathology committee
• Thomas Montine: chair, co-PI• Eric Reiman: co-PI• Dennis Dickson• Matthew Frosch• Bernadino Ghetti• Brad Hyman• Julie Schneider• John Trojanowski
• Walter Kukull NACC• Gerard Schellenberg ADGC
NACC
ADGC
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
Selection of samples for GWAS
UDS SamplesClinical committee
• John Morris chair, co-PI• Debbie Tsuang co-PI• Thomas Bird• Helena Chui• Jeffrey Cummings• Charlie DeCarli• Steven Ferris • Douglas Galasko• Neil Graff-Radford• Richard Mayeux• Elaine Peskind• John Ringman• Sandra Weintraub• Walter Kukull NACC• Gerard Schellenberg ADGC
subject lists
NACC
ADGC
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
subject lists
NCRAD
DNAtissue
Tatiana Foroud
NACC
ADGC
ADGC
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
subject lists
DNAtissue
list of samples received
NACC
ADGC
NCRAD
ADGC
29 ADCs
data
cleaning
Alzheimer’s Disease Center Samples
subject lists
DNAtissue
list of samples received
Genotyping site
CHOP
DNA
NACC
ADGC
NCRAD
ADGC
Alzheimer’s Disease Center Samples
29 ADCs
data
cleaning
subject lists
DNAtissue
list of samples received
Genotyping site
CHOP
DNA
ADGCUPenn
genotype data
phenotype data
NACC
ADGC
NCRAD
ADGC
OTHER GWASDATASETS
Special analysis groups (SAGs)
• clean genotype data• impute genotypes• merge genotype/phenotype data• Perform primary analyses
University of Miami analysis group
Boston University analysis group
Margaret Pericak-Vance Lindsay Farrer
Genotyping
ADGCUPenn
genotype data
phenotype data data
Special analysis groups (SAGs)
• clean genotype data• impute genotypes• merge genotype/phenotype data• Perform primary analyses
University of Miami analysis group
Boston University analysis group
Margaret Pericak-Vance Lindsay Farrer
data
dbGaP
NIAGADUPenn
ApoEGWAS SNPsCNV data
ADCs
publication
ADGC Website
http://alois.med.upenn.edu/adgc/
Autopsy samples
genotyped by the
ADGC
Cases: 2,901Controls: 211
Autopsy samples
with NACC data
Overlap with
other studies
Remaining
samples
Samples received
Percent
recovered
4,727
764
3,963
3,773
95.2%
Clinical samples
genotyped by the
ADGC
Cases: 1,216Controls: 1,791
Clinical UDS
samples in NACC
Samples received
Demented (AD)
Normal
MCI
excluded
17,270
1,543
6,033
2,130
1,554
806
CSF samples
genotyped by the
ADGC
Cases: 98Controls: 155MCI: 11Other: 119Total: 383
Pending: 76
Current total: 459
Projected Total: >600
ADGC Study to Replicate CR1, CLU and PICALM
Association Findings in European Consortia GWAS
CohortNumber
of Cases
Number
of
autopsies
Mean
onset age
(SD)
Number
of
Controls
Number
of
autopsies
Mean age at
last exam
(SD)
Total
Percent of
Ethnic
group
Caucasian Subjects
ADC 1,595 1,421 73 (7.7) 553 134 77 (8.7) 2,148 17%
ADNI 286 0 74 (8.1) 195 0 78 (5.4) 481 4%
CAMP 127 0 79 (7.9) 105 0 76 (7.8) 232 2%
FHS 197 0 83 (6.4) 2,392 0 73 (7.5) 2,589 20%
UM/VU/MSSM 1,170 370 74 (7.7) 1,169 75 74 (7.6) 2,339 18%
MIRAGE 560 0 71 (6.5) 790 0 72 (7.1) 1,350 10%
NIA LOAD 993 367 72 (6.9) 884 45 76 (8.4) 1,877 14%
OHSU 187 215 87 (7.3) 429 461 86 (7.2) 616 5%
TGEN 820 613 80 (8.3) 517 377 83 (8.9) 1,337 10%
Totals 5,935 2,986 7,034 1,092 12,969 100%
African American Subjects
ADC 61 61 75 (7.0) 63 63 76 (6.2) 124 14%
JHU 221 0 77 (6.6) 186 0 78 (6.6) 407 45%
MIRAGE 180 0 70 (8.9) 200 0 71 (10.0) 380 42%
Totals 462 61 449 63 911 100%
Arab Subjects
Wadi Ara 124 0 78 (7.9) 142 0 72 (6.0) 266 100%
Caribbean Hispanic Subjects
Columbia 549 8 80 (8.0) 544 0 79 (6.4) 1,093 100%
All Ethnic Groups
Totals 7,070 3,055 8,169 1,155 15,239
SD: Standard deviation; ADC: Alzheimer Disease Centers cohort; ADNI: Alzheimer Disease Neuroimaging Initiative cohort; FHS.: Framingham Heart Study
cohort; UM/VU/MSSM: University of Miami/Vanderbilt University/Mt. Sinai School of Medicine cohort; MIRAGE: Multi Institutional Research on Alzheimer's
Genetic Epidemiology cohort; NIA LOAD: National Institute on Aging Late-onset Alzheimer Disease cohort; OHSU: Oregon Health Sciences University cohort;
TGEN: Translational Genomics Research Institute cohort
Unadjusted adjusted age sex & APOE
SNP MA MAF OR 95% CI P‡ OR 95% CI P‡
CR1
rs3818361 A 0.26 1.14 1.07 - 1.22 6.1x10-5 1.15 1.07 - 1.24 0.0002
rs6701713 A 0.26 1.14 1.07 - 1.22 8.8x10-5 1.15 1.07 - 1.24 0.0002
rs1408077 A 0.26 1.14 1.07 - 1.22 0.0001 1.16 1.07 - 1.25 0.0002
CLU
rs7012010 C 0.39 1.10 1.03 - 1.17 0.0025 1.10 1.02 - 1.17 0.0081
rs3087554 C 0.16 1.00 0.92 - 1.09 0.92 0.98 0.89 - 1.08 0.71
rs11136000 T 0.43 0.91 0.85 - 0.96 0.0007 0.92 0.86 - 0.98 0.0096
rs9331888 G 0.25 0.99 0.92 - 1.06 0.76 0.99 0.91 - 1.07 0.74
rs7982 T 0.38 0.87 0.81 - 0.94 0.0002 0.89 0.83 - 0.97 0.0046
PICALM
rs532470 G 0.49 1.06 1.00 - 1.11 0.048 1.02 0.96 - 1.09 0.47
rs592297 C 0.20 0.92 0.86 - 0.99 0.02 0.96 0.89 - 1.04 0.33
rs677909 C 0.40 0.88 0.83 - 0.94 3.3x10-5 0.94 0.88 - 1.00 0.056
rs636848 G 0.24 1.02 0.96 - 1.08 0.6 1.00 0.93 - 1.07 0.98
rs541458 C 0.39 0.88 0.83 - 0.93 2.6x10-5 0.94 0.88 - 1.00 0.048
rs561655 G 0.29 0.89 0.84 - 0.94 3.4x10-5 0.92 0.87 - 0.99 0.017
rs543293 A 0.36 0.88 0.83 - 0.93 2.3x10-5 0.92 0.86 - 0.98 0.015
rs7941541 G 0.28 0.89 0.83 - 0.95 0.0007 0.95 0.88 - 1.03 0.21
rs3851179 T 0.35 0.89 0.84 - 0.94 3.9x10-5 0.93 0.87 - 0.99 0.026
Jun et al. Arch Neurol 2010 In press.
Gene/SNP
APOE e4 (-)† APOE e4 (+)† SNP*APOE interaction¶
OR 95% CI P-value OR 95% CI P-value OR 95% CI P-value
CR1
rs3818361 1.10 1.02 - 1.19 0.0170 1.14 1.03 - 1.26 0.0120 1.01 0.99 - 1.03 0.2800
rs6701713 1.10 1.01 - 1.19 0.0210 1.14 1.03 - 1.26 0.0110 1.01 0.99 - 1.04 0.2800
rs1408077 1.06 1.00 - 1.12 0.0360 1.15 1.03 - 1.27 0.0099 1.06 0.97 - 1.16 0.1900
CLU
rs7012010 1.10 1.00 - 1.20 0.0430 1.05 1.00 - 1.10 0.0640 1.03 0.94 - 1.12 0.5100
rs3087554 1.01 0.90 - 1.14 0.8800 1.00 0.84 - 1.18 0.9700 1.00 0.82 - 1.22 1.0000
rs11136000 0.91 0.84 - 0.98 0.0150 0.93 0.84 - 1.03 0.1700 0.98 0.92 - 1.06 0.6500
rs9331888 1.03 0.93 - 1.14 0.5300 0.92 0.80 - 1.05 0.1900 0.89 0.77 - 1.04 0.1400
rs7982 0.87 0.79 - 0.97 0.0092 0.92 0.81 - 1.05 0.2200 1.06 0.91 - 1.24 0.4800
PICALM
rs532470 0.99 0.92 - 1.08 0.8900 1.12 1.01 - 1.24 0.0300 1.11 0.98 - 1.25 0.1000
rs592297 1.04 0.97 - 1.11 0.3200 0.90 0.79 - 1.03 0.1200 0.85 0.73 - 1.00 0.0480
rs677909 0.99 0.91 - 1.08 0.8000 0.86 0.77 - 0.96 0.0062 0.86 0.75 - 0.98 0.0260
rs636848 0.96 0.88 - 1.06 0.4400 1.07 0.95 - 1.21 0.2700 1.07 0.92 - 1.23 0.3900
rs541458 0.99 0.91 - 1.08 0.8100 0.86 0.77 - 0.96 0.0066 0.86 0.75 - 0.98 0.0270
rs561655 0.97 0.89 - 1.06 0.5000 0.83 0.75 - 0.93 0.0009 0.82 0.73 - 0.93 0.0024
rs543293 1.00 0.92 - 1.09 0.9800 0.83 0.74 - 0.93 0.0011 0.81 0.71 - 0.93 0.0026
rs7941541 0.98 0.90 - 1.08 0.7300 0.90 0.79 - 1.02 0.0990 0.89 0.79 - 0.99 0.0360
rs3851179 0.99 0.91 - 1.07 0.7300 0.86 0.77 - 0.95 0.0034 0.84 0.74 - 0.95 0.0068
Jun et al. Arch Neurol 2010 In press.
Cohorts for ADGC GWAS
Cohort Ethnicity Cases Controls Total Platform
CR1, CLU,
Picalm
Replication
ADGC
GWAS
ADGC
GWAS
replication
AA
ADNI Caucasian 291 189 480 Illumina 550K X X
OHSU Caucasian 424 169 593 Illumina 300K X X
NIA LOAD Caucasian 1,839 1,983 3,822 Illumina 610Q X X
Miami/Vanderbilt/Mt.Sinai Caucasian 1,168 1,168 2,336 Illumina 550K X X
MIRAGE Caucasian 603 885 1,488 Illumina 660 Quad X X
ADC Caucasian 2,321 916 3,237 Illumina 660 Quad X X
GSK Caucasian 656 641 1,297 Affymetrix 550K X
TGEN Caucasian 744 420 1,164 Affymetrix 6.0 X X
eMERGE (ACT) Caucasian 567 1,701 2,268 Illumina 660 Quad X
Washington Univ. Caucasian 406 178 584 Illumina 610 Quad X
CAMP Amish 127 105 232 Illumina 550K X X
Framingham Caucasian 197 2,392 2,589 Affymetrix 550K X X
NIA-ADC June 2010 Caucasian 1,015 697 1,712 Illumina Omni Express X
Mayo Clinic Caucasian 844 1,255 2,099 Illumina 300K X
ROS/MAP Caucasian 495 1,153 1,648 Affymetrix 6.0 X
Univ. Pittsburgh Caucasian 1500 1,500 3,000 X
MIRAGE AA 260 240 500 Illumina 660 Quad X X
NIA-ADC AA 61 63 124 Illumina 660 Quad X X
NIA-ADC June 2010 AA 183 123 306 Illumina Omni Express X
GenerAAtions AA 250 218 468 Illumina 660 Quad X X
Columbia Hispanic 549 544 1,093 Illumina 650Y X
Wadi Ara Israeli-
Arab124 142 266 Illumina 370K X
Cases Controls Total
Caucasian Discovery * 8,613 8,072 16,685
Caucasian Replication 4,584 7,280 11,864
African American † 754 1,398 2,152
* ~ 2-fold larger than the largest of published AD GWAS
discovery samples
† effort underway to increase this sample 3-4 fold
Cohorts for ADGC GWAS
ADGC Projects in progress and on-deck
• GWAS in Caucasians
• Assemble large African American cohort for GWAS
• GWAS of endophenotypes in case/control group (e.g., biomarkers, neuropathological traits)
• Prospective cohort studies
David Bennett Rush University Medical Center, Chicago, IL Deborah Blacker Massachusetts General, Boston, MALindsay Farrer Boston UniversityTatiana Foroud Indiana University, Indianapolis, INAlison Goate Washington University, St Louis, MOJonathan Haines Vanderbilt, Nashville, TNHakon Hakonarson Children’s Hospital of Philadelphia, Philadelphia, PAWalter Kukull University of Washington, Seattle, WAKathryn Lunetta Boston University, Boston, MA Eden Martin University of Miami, Miami, FLRichard Mayeux Columbia University, New York, NYThomas Montine University of Washington, Seattle, WAJohn Morris Washington University, St Louis, MO Margaret Pericak-Vance University of Miami, Miami, FLEric Reiman Banner Alzheimer’s Institute, Phoenix, AZAndrew Saykin Indiana University, Indianapolis, INGerard Schellenberg (PI) University of Pennsylvania, Philadelphia, PADebbie Tsuang University of Washington, Seattle, WA
Laura Cantwell University of Pennsylvania, Philadelphia, PALi-San Wang University of Pennsylvania, Philadelphia, PA
Funding: NIA - UO1/GO grants, Boston non-profit foundation
KUDOS
Boston University
Gyungah JunJacki BurosBadri Vardarajan
University of Miami
Gary BeechamAdam NajPaul Gallins
Special Thanks
The Clinical and Neuropathology
Cores of the NIA-sponsored
Alzheimer Disease Centers