TY - JOUR
T1 - Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes
AU - Jun, Gyungah
AU - Naj, Adam C.
AU - Beecham, Gary W.
AU - Wang, Li San
AU - Buros, Jacqueline
AU - Gallins, Paul J.
AU - Buxbaum, Joseph D.
AU - Ertekin-Taner, Nilufer
AU - Fallin, M. Daniele
AU - Friedland, Robert
AU - Inzelberg, Rivka
AU - Kramer, Patricia
AU - Rogaeva, Ekaterina
AU - St George-Hyslop, Peter
AU - Cantwell, Laura B.
AU - Dombroski, Beth A.
AU - Saykin, Andrew J.
AU - Reiman, Eric M.
AU - Bennett, David A.
AU - Morris, John C.
AU - Lunetta, Kathryn L.
AU - Martin, Eden R.
AU - Montine, Thomas J.
AU - Goate, Alison M.
AU - Blacker, Deborah
AU - Tsuang, Debby W.
AU - Beekly, Duane
AU - Cupples, L. Adrienne
AU - Hakonarson, Hakon
AU - Kukull, Walter
AU - Foroud, Tatiana M.
AU - Haines, Jonathan
AU - Mayeux, Richard
AU - Farrer, Lindsay A.
AU - Pericak-Vance, Margaret A.
AU - Schellenberg, Gerard D.
PY - 2010/12
Y1 - 2010/12
N2 - 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 ofADand 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. APOEε4 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 APOEε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOEε4, and an interaction term showed significant interaction between presence or absence of APOEε4 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 ε4-positive subjects. Thus, APOE and PICALM synergistically interact.
AB - 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 ofADand 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. APOEε4 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 APOEε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOEε4, and an interaction term showed significant interaction between presence or absence of APOEε4 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 ε4-positive subjects. Thus, APOE and PICALM synergistically interact.
UR - http://www.scopus.com/inward/record.url?scp=77957909886&partnerID=8YFLogxK
U2 - 10.1001/archneurol.2010.201
DO - 10.1001/archneurol.2010.201
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C2 - 20697030
AN - SCOPUS:77957909886
SN - 0003-9942
VL - 67
SP - 1473
EP - 1484
JO - Archives of Neurology
JF - Archives of Neurology
IS - 12
ER -