Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes
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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 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.
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The record
- Venue
- Archives of Neurology
- Topic
- Dementia and Cognitive Impairment Research
- Field
- Medicine
- Canadian institutions
- —
- Funders
- National Center for Research ResourcesNational Cancer InstituteNational Human Genome Research InstituteNational Institute of Mental HealthNational Heart, Lung, and Blood InstituteNational Institute on AgingFoundation for the National Institutes of HealthUniversity of California, IrvineUniversity of California, San DiegoNational Natural Science Foundation of ChinaUniversity of California, DavisNational Institute of Biomedical Imaging and BioengineeringUniversity of California, Los AngelesNational Institutes of HealthNorthwestern UniversityYork UniversityNational Institute of Neurological Disorders and StrokeUniversity of PittsburghUniversity of WashingtonJohns Hopkins UniversityUniversity of California, San FranciscoTranslational Genomics Research InstituteEmory UniversityUniversity of PennsylvaniaVanderbilt UniversityWellcome TrustUniversity of Southern CaliforniaDana FoundationAlzheimer's AssociationNorthern California Institute for Research and EducationMassachusetts General Hospital
- Keywords
- Apolipoprotein EOdds ratioGenotypeSingle-nucleotide polymorphismSNPInternal medicineClusterinOncologyMedicineBiologyGeneticsDiseaseGene
- Has abstract in OpenAlex
- yes