Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.
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Jun Gyungah, Naj Adam C, Beecham Gary W, Wang Li-San, Buros Jacqueline, Gallins Paul J, Buxbaum Joseph D, Ertekin-Taner Nilufer, Fallin M Daniele, Friedland Robert, Inzelberg Rivka, Kramer Patricia, Rogaeva Ekaterina, St George-Hyslop Peter, Alzheimer's Disease Genetics Consortium, Cantwell Laura B, Dombroski Beth A, Saykin Andrew J, Reiman Eric M, Bennett David A, Morris John C, Lunetta Kathryn L, Martin Eden R, Montine Thomas J, Goate Alison M, Blacker Deborah, Tsuang Debby W, Beekly Duane, Cupples L Adrienne, Hakonarson Hakon, Kukull Walter, Foroud Tatiana M, Haines Jonathan, Mayeux Richard, Farrer Lindsay A, Pericak-Vance Margaret A, Schellenberg Gerard D
Аннотация
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 ε4 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 ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ε4, and an interaction term showed significant interaction between presence or absence of APOE ε4 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.