An examination of regulatory function for GWAS-confirmed and suggestive loci of late-onset...
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Canada; 3 University of British Columbia Hospital, Vancouver, British Columbia, Canada. Contact e-mail: [email protected] Background: Recent genome wide association studies (GWAS) revealed several new risk loci for late-onset Alzheimer disease (LOAD). We under- took genetic case-control studies to examine the role of 10 promising novel AD loci (CR1, CLU, PICALM, TOMM40, CD33, EPHA1, MS4A4A, CD2AP, BIN1, and ABCA7) in participants from 2 large cohorts: Canadian Study of Health and Aging (CSHA) and A Canadian Collaborative Cohort of Cognitive Impairment and Related Dementia (ACCORD) using prevalent and incident cases of AD. Methods: We included subjects (age 65) from both cohorts. Those who developed AD during longitudinal observa- tion of the cohorts from CSHA or ACCORD were defined as incident cases (IC), whereas individual with AD at entry into CSHA or ACCORD were de- fined as prevalent cases (PC). IC and PC subjects were genotyped and com- pared to age and ethnicity matched subjects with no cognitive impairment (NCI). Genotypes were obtained using TaqMan assays, and chi-squared test was used to compare allele and genotype frequencies. Results: Our PC study comparing subjects with AD at baseline assessment (n¼428) with NCI participants (n¼524) revealed significant association of LOAD with rs6656401 (CR1), rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33), which were robust to influence of age and APOE ε4-status. The IC study comparing patients who developed AD during observation of the cohorts (n¼152) with NCI found that rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of incident AD independent of APOE ε4-status. Furthermore, pooled analysis on all participants including AD (PC & IC) vs. those who remained cognitively stable found that rs3851179 (PICALM) contributes additional AD suscepti- bility risk. Conclusions: This study thus provides evidence that in Cana- dians of European descent, CR1, PICALM, TOMM40, BIN, and CD33 are contributing loci to LOAD risk in addition to APOE genotype. P3-007 AN EXAMINATIONOF REGULATORY FUNCTION FOR GWAS-CONFIRMED AND SUGGESTIVE LOCI OF LATE-ONSET ALZHEIMER’S DISEASE Samantha Rosenthal 1 , Michael Barmada 2 , Xingbin Wang 2 , Yesim Demirci 2 , Oscar Lopez 3 , Ilyas Kamboh 4 , 1 University of Pittsburgh, Graduate School of Public Health, Department of Human Genetics, Pittsburgh, Pennsylvania, United States; 2 University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania, United States; 3 University of Pittsburgh; Alzheimer’s Disease Research Center, Pittsburgh, Pennsylvania, United States; 4 University of Pittsburgh, Graduate School of Public Health; Alzheimer’s Disease Research Center, Pittsburgh, Pennsylvania, United States. Contact e-mail: [email protected] Background: Given the incredible number of genome-wide significant SNPs found outside of coding regions, the advent of a tool such as Regulo- meDB is not only helpful but essential to further our understanding of inter- genic and intronic changes that may alter regulatory function, gene expression, and ultimately, disease phenotypes. A more thorough knowl- edge of the regulatory elements that affect gene expression is of particular desire for multifactorial diseases which tend to show only moderate associ- ations among a number of genes for a given disease. The complex neurode- generative disorder late-onset Alzheimer’s disease (LOAD) is one such disease that may be better understood by closer examination of SNPs affect- ing transcription. Methods: Currently, ten loci (APOE, BIN1, CLU, EPHA1, PICALM, CD2AP, CD33, ABCA7, MS4A4A/MS4A6E, and CR1) have been identified as risk loci for LOAD. In this study, we sought to determine potential regulatory functions of genome-wide significant SNPs for nine of these ten loci (APOE excluded), as well as suggestive loci, from previously published GWAS studies of LOAD using Regulome DB (http://regulomedb.org). Results: We identified 140 SNPs in linkage disequilibrium (r 2> 0.8) with the 31 SNPs of interest for a total pool of 171 SNPs. All 171 SNPs were input into RegulomeDB resulting in 14 SNPs with RegulomeDB scores of 2b or lower indicating the SNP has a high likelihood of affecting gene expression. Of these 14, the SNP with the most evidence for regulatory function (RegulomeDB score¼1b) was an intergenic SNP that falls in the MS4A region. This SNP has previously been identified as being an eQTL for MS4A4A, and looks to be involved in regulating binding of transcription factors through TCF11:MafG and NFE2L2 motifs. The MS4A region was represented by 6 additional SNPs with a score of 1f. Additional loci with a Regulome DB score of 2a or 2b fell into the CD2AP, CLU, ABCA7, and PICALM gene regions. We also ob- served strong functional evidence for SNPs in two suggestive loci, SLC28A1 (Regulome DB score¼1f) and HRK/RNFT2 (Regulome DB score¼2a). Conclusions: These results provide further possibilities for ex- plaining the association seen between non-coding SNPs of associated risk loci and LOAD. P3-008 GENOME-WIDE ANALYSIS OF GENETIC VARIANTS ASSOCIATED WITH DEPRESSIVE SYMPTOMS IN OLDER ADULTS Kwangsik Nho 1 , Shanker Swaminathan 1 , Sungeun Kim 1 , Shannon Risacher 1 , Vijay Ramanan 1 , Li Shen 1 , Scott Mackin 2 , Paul Aisen 3 , Ronald Petersen 4 , Michael Weiner 5 , Brenna McDonald 6 , Martin Farlow 6 , Bernardino Ghetti 1 , Sujuan Gao 7 , Andrew Saykin 8 , Andrew Saykin 9 , Robert Green 10 , 1 Indiana University School of Medicine, Indianapolis, Indiana, United States; 2 University of California, San Francisco, San Francisco, California, United States; 3 UCSD, La Jolla, California, United States; 4 Mayo Clinic Rochester, Rochester, Minnesota, United States; 5 Center for Imaging of Neurodegenerative Diseases, VA Medical Center and UCSF, San Francisco, California, United States; 6 Indiana University School of Medicine, Indianapolis, Indiana, United States; 7 IUSM, Indianapolis, Indiana, United States; 8 Indiana University, Indianapolis, Indiana, United States; 9 Indiana University School of Medicine, Indianapolis, Indiana, United States; 10 University of Pittsburgh Schools of Nursing and Medicine, Pittsburgh, Pennsylvania, United States. Contact e-mail: [email protected] Background: Neuropsychiatric symptoms such as depression are common in older adults and particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be as high as 50% (Jansson et al. 2004), genome wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in depressive symptoms have had limited success. Nevertheless, GWAS have implicated CNVs in Alzheimer’s disease (AD) as well as neuropsychi- atric disorders such as schizophrenia and autism. Methods: In the Table 2 Total CNV Burden Test in ADNI1 Case (N¼134) Control (N¼241) P value Deletion 1,355 2,170 0.03 Duplication 517 998 0.83 Both 1,872 3,168 0.09 Table 1 GWAS results in the discovery sample (ADNI1) and meta-analysis result (ADNI1, HRS, and IMAS) ADNI-1 Meta-Analysis SNP Gene N b P value N b P value rs62020725 IQGAP1 748 0.4488 2.878e-08 8494 0.1351 1.695e-05 Figure 1. Plot of meta-analysis results for rs62020725 using 3 independent cohorts: ADNI1, the Health and Retirement Study (HRS), and Indiana Memory and Aging Study (IMAS). Tuesday, July 16, 2013:Poster Presentations: P3 P552
Transcript of An examination of regulatory function for GWAS-confirmed and suggestive loci of late-onset...
Tuesday, July 16, 2013: Poster Presentations: P3P552
Canada; 3University of British Columbia Hospital, Vancouver, British
Columbia, Canada. Contact e-mail: [email protected]
Background: Recent genome wide association studies (GWAS) revealed
several new risk loci for late-onset Alzheimer disease (LOAD). We under-
took genetic case-control studies to examine the role of 10 promising novel
AD loci (CR1, CLU, PICALM, TOMM40, CD33, EPHA1, MS4A4A,
CD2AP, BIN1, and ABCA7) in participants from 2 large cohorts: Canadian
Study of Health andAging (CSHA) and ACanadianCollaborative Cohort of
Cognitive Impairment and Related Dementia (ACCORD) using prevalent
and incident cases of AD. Methods: We included subjects (age �65)
from both cohorts. Those who developed AD during longitudinal observa-
tion of the cohorts from CSHA or ACCORD were defined as incident cases
(IC), whereas individual with AD at entry into CSHA or ACCORDwere de-
fined as prevalent cases (PC). IC and PC subjects were genotyped and com-
pared to age and ethnicity matched subjects with no cognitive impairment
(NCI). Genotypes were obtained using TaqMan assays, and chi-squared
test was used to compare allele and genotype frequencies. Results: Our
PC study comparing subjects with AD at baseline assessment (n¼428)
with NCI participants (n¼524) revealed significant association of LOAD
with rs6656401 (CR1), rs3818361 (CR1), rs2075650 (TOMM40),
rs7561528 (BIN1), and rs3865444 (CD33), which were robust to influence
of age and APOE ε4-status. The IC study comparing patients who developed
AD during observation of the cohorts (n¼152) with NCI found that
rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of incident
AD independent of APOE ε4-status. Furthermore, pooled analysis on all
participants including AD (PC & IC) vs. those who remained cognitively
stable found that rs3851179 (PICALM) contributes additional AD suscepti-
bility risk. Conclusions: This study thus provides evidence that in Cana-
dians of European descent, CR1, PICALM, TOMM40, BIN, and CD33
are contributing loci to LOAD risk in addition to APOE genotype.
P3-007 AN EXAMINATION OF REGULATORY FUNCTION
FORGWAS-CONFIRMEDAND SUGGESTIVE LOCI
OF LATE-ONSETALZHEIMER’S DISEASE
Table 2
Total CNV Burden Test in ADNI1
Case (N¼134) Control (N¼241) P value
Deletion 1,355 2,170 0.03
Duplication 517 998 0.83
Both 1,872 3,168 0.09
Table 1
GWAS results in the discovery sample (ADNI1) and meta-analysis result
(ADNI1, HRS, and IMAS)
ADNI-1 Meta-Analysis
SNP Gene N b P value N b P value
rs62020725 IQGAP1 748 0.4488 2.878e-08 8494 0.1351 1.695e-05
Figure 1. Plot of meta-analysis results for rs62020725 using 3 independent
cohorts: ADNI1, the Health and Retirement Study (HRS), and Indiana
Memory and Aging Study (IMAS).
Samantha Rosenthal1, Michael Barmada2, Xingbin Wang2,
Yesim Demirci2, Oscar Lopez3, Ilyas Kamboh4, 1University of Pittsburgh,
Graduate School of Public Health, Department of Human Genetics,
Pittsburgh, Pennsylvania, United States; 2University of Pittsburgh,
Graduate School of Public Health, Pittsburgh, Pennsylvania, United States;3University of Pittsburgh; Alzheimer’s Disease Research Center, Pittsburgh,
Pennsylvania, United States; 4University of Pittsburgh, Graduate School of
Public Health; Alzheimer’s Disease Research Center, Pittsburgh,
Pennsylvania, United States. Contact e-mail: [email protected]
Background: Given the incredible number of genome-wide significant
SNPs found outside of coding regions, the advent of a tool such as Regulo-
meDB is not only helpful but essential to further our understanding of inter-
genic and intronic changes that may alter regulatory function, gene
expression, and ultimately, disease phenotypes. A more thorough knowl-
edge of the regulatory elements that affect gene expression is of particular
desire for multifactorial diseases which tend to show only moderate associ-
ations among a number of genes for a given disease. The complex neurode-
generative disorder late-onset Alzheimer’s disease (LOAD) is one such
disease that may be better understood by closer examination of SNPs affect-
ing transcription. Methods: Currently, ten loci (APOE, BIN1, CLU,
EPHA1, PICALM, CD2AP, CD33, ABCA7, MS4A4A/MS4A6E, and
CR1) have been identified as risk loci for LOAD. In this study, we sought
to determine potential regulatory functions of genome-wide significant
SNPs for nine of these ten loci (APOE excluded), as well as suggestive
loci, from previously published GWAS studies of LOAD using Regulome
DB (http://regulomedb.org). Results: We identified 140 SNPs in linkage
disequilibrium (r 2> 0.8) with the 31 SNPs of interest for a total pool of
171 SNPs. All 171 SNPs were input into RegulomeDB resulting in
14 SNPs with RegulomeDB scores of 2b or lower indicating the SNP has
a high likelihood of affecting gene expression. Of these 14, the SNP with
the most evidence for regulatory function (RegulomeDB score¼1b) was
an intergenic SNP that falls in the MS4A region. This SNP has previously
been identified as being an eQTL for MS4A4A, and looks to be involved
in regulating binding of transcription factors through TCF11:MafG and
NFE2L2 motifs. The MS4A region was represented by 6 additional SNPs
with a score of 1f. Additional loci with a Regulome DB score of 2a or 2b
fell into the CD2AP, CLU, ABCA7, and PICALMgene regions.We also ob-
served strong functional evidence for SNPs in two suggestive loci,
SLC28A1 (Regulome DB score¼1f) and HRK/RNFT2 (Regulome DB
score¼2a). Conclusions: These results provide further possibilities for ex-
plaining the association seen between non-coding SNPs of associated risk
loci and LOAD.
P3-008 GENOME-WIDE ANALYSIS OF GENETIC
VARIANTS ASSOCIATEDWITH DEPRESSIVE
SYMPTOMS IN OLDER ADULTS
Kwangsik Nho1, Shanker Swaminathan1, Sungeun Kim1,
Shannon Risacher1, Vijay Ramanan1, Li Shen1, Scott Mackin2, Paul Aisen3,
Ronald Petersen4, Michael Weiner5, Brenna McDonald6, Martin Farlow6,
Bernardino Ghetti1, Sujuan Gao7, Andrew Saykin8, Andrew Saykin9,
Robert Green10, 1Indiana University School of Medicine, Indianapolis,
Indiana, United States; 2University of California, San Francisco, San
Francisco, California, United States; 3UCSD, La Jolla, California, United
States; 4Mayo Clinic Rochester, Rochester, Minnesota, United States;5Center for Imaging of Neurodegenerative Diseases, VA Medical Center
and UCSF, San Francisco, California, United States; 6Indiana University
School of Medicine, Indianapolis, Indiana, United States; 7IUSM,
Indianapolis, Indiana, United States; 8Indiana University, Indianapolis,
Indiana, United States; 9Indiana University School of Medicine,
Indianapolis, Indiana, United States; 10University of Pittsburgh Schools of
Nursing and Medicine, Pittsburgh, Pennsylvania, United States.
Contact e-mail: [email protected]
Background: Neuropsychiatric symptoms such as depression are common
in older adults and particularly prevalent in those with or at elevated risk for
dementia. Although the heritability of depression is estimated to be as high
as 50% (Jansson et al. 2004), genome wide association studies (GWAS) of
single nucleotide polymorphisms (SNPs) and copy number variants (CNVs)
in depressive symptoms have had limited success. Nevertheless, GWAS
have implicated CNVs in Alzheimer’s disease (AD) as well as neuropsychi-
atric disorders such as schizophrenia and autism. Methods: In the
