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

Gyungah Jun, Adam C. Naj, Gary W. Beecham, Li San Wang, Jacqueline Buros, Paul J. Gallins, Joseph D. Buxbaum, Nilufer Ertekin-Taner, M. Daniele Fallin, Robert Friedland, Rivka Inzelberg, Patricia Kramer, Ekaterina Rogaeva, Peter St George-Hyslop, Laura B. Cantwell, Beth A. Dombroski, Andrew J. Saykin, Eric M. Reiman, David A. Bennett, John C. MorrisKathryn L. Lunetta, Eden R. Martin, Thomas J. Montine, Alison M. Goate, Deborah Blacker, Debby W. Tsuang, Duane Beekly, L. Adrienne Cupples, Hakon Hakonarson, Walter Kukull, Tatiana M. Foroud, Jonathan Haines, Richard Mayeux, Lindsay A. Farrer, Margaret A. Pericak-Vance, Gerard D. Schellenberg

Research output: Contribution to journalArticle

288 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1473-1484
Number of pages12
JournalArchives of neurology
Volume67
Issue number12
DOIs
StatePublished - Dec 2010

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

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    Jun, G., Naj, A. C., Beecham, G. W., Wang, L. S., Buros, J., Gallins, P. J., Buxbaum, J. D., Ertekin-Taner, N., Fallin, M. D., Friedland, R., Inzelberg, R., Kramer, P., Rogaeva, E., St George-Hyslop, P., Cantwell, L. B., Dombroski, B. A., Saykin, A. J., Reiman, E. M., Bennett, D. A., ... Schellenberg, G. D. (2010). Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Archives of neurology, 67(12), 1473-1484. https://doi.org/10.1001/archneurol.2010.201