Dataset Information

Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

ABSTRACT: OBJECTIVES:To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. DESIGN:Association study of AD and CLU, PICALM, CR1, and APOE genotypes. SETTING:Academic research institutions in the United States, Canada, and Israel. PARTICIPANTS:Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. RESULTS:Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE ?4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE ?4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ?4, and an interaction term showed significant interaction between presence or absence of APOE ?4 and PICALM. CONCLUSIONS:We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ?4-positive subjects. Thus, APOE and PICALM synergistically interact.

SUBMITTER: Jun G

PROVIDER: S-EPMC3048805 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

Jun Gyungah G Naj Adam C AC Beecham Gary W GW Wang Li-San LS Buros Jacqueline J Gallins Paul J PJ Buxbaum Joseph D JD Ertekin-Taner Nilufer N Fallin M Daniele MD Friedland Robert R Inzelberg Rivka R Kramer Patricia P Rogaeva Ekaterina E St George-Hyslop Peter P Cantwell Laura B LB Dombroski Beth A BA Saykin Andrew J AJ Reiman Eric M EM Bennett David A DA Morris John C JC Lunetta Kathryn L KL Martin Eden R ER Montine Thomas J TJ Goate Alison M AM Blacker Deborah D Tsuang Debby W DW Beekly Duane D Cupples L Adrienne LA Hakonarson Hakon H Kukull Walter W Foroud Tatiana M TM Haines Jonathan J Mayeux Richard R Farrer Lindsay A LA Pericak-Vance Margaret A MA Schellenberg Gerard D GD

Archives of neurology 20100809 12

<h4>Objectives</h4>To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes.<h4>Design</h4>Association study of AD and CLU, PICALM, CR1, and APOE genotypes.<h4>Setting</h4>Academic research institutions in the United States, Canada, and Israel.<h4>Participants</h4>Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal ...[more]

PMID: 20697030

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Project description:BackgroundGenetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects.MethodsWe pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale-Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E ε4 dosage.ResultsWe identified nominally significant or suggestive associations between the LOAD-risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068-.046, β = -2.7 to -1.2). The LOAD-protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099-.027, β = 0.31-0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed.ConclusionThese results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD-protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.

Dataset Information

Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

Publications

Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

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