. Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes. Arch Neurol. 2010 Aug 9;1(1):1-20.


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 epsilon4 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 epsilon4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE epsilon4, and an interaction term showed significant interaction between presence or absence of APOE epsilon4 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 epsilon4-positive subjects. Thus, APOE and PICALM synergistically interact.


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  1. Last year we published a GWAS of AD, and, together with an independent study, identified CLU, PICALM, and CR1 as susceptibility loci for Alzheimer disease (see Harold et al., 2009 and Lambert et al., 2009). These associations are replicated in the present study by Gyungah Jun and colleagues of the Alzheimer's Disease Genetics Consortium (ADGC), and together with similar recent studies (see Carrasquillo et al., 2010 and Corneveaux et al., 2010), provide additional confirmation that these are genuine susceptibility loci.

    However, Jun et al. also report a significant ApoE-PICALM statistical interaction such that the significant association at the PICALM locus is predominantly observed in ApoE4 carriers. This is in contrast with the results from our GWAS, where no significant interaction with ApoE was observed (Stage1 sample: ApoE4 x PICALM rs3851179 interaction term P = 0.83; Stage 2 sample: P = 0.25). Restricting our analysis to the subset of individuals with available ApoE genotypes, our results for rs3851179 without adjustment for ApoE are: Stage 1 P = 6.4 x 10-5, OR = 0.85; Stage 2 P = 0.012, OR = 0.88); when adjusted for ApoE, the significance is only slightly reduced (Stage 1 P = 5.7 x 10-4, OR = 0.86; Stage 2 P = 0.049, OR = 0.90). Moreover, Carrasquillo et al. (2010) report significant association of rs3851179 with AD after ApoE adjustment (P = 1.3 x 10-5, OR = 0.80), and report that the results “stay essentially the same when no covariates are used, (i.e., when no adjustment is made for sex, age, and ApoE4 status).”

    Thus, the putative ApoE-PICALM epistatic interaction does not appear to be consistent across the datasets examined to date, although the intriguing possibility that ApoE and PICALM are involved in a common pathogenic pathway warrants further investigation.


    . Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. PubMed.

    . Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1094-9. PubMed.

    . Replication of CLU, CR1, and PICALM associations with alzheimer disease. Arch Neurol. 2010 Aug;67(8):961-4. PubMed.

    . Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet. 2010 Aug 15;19(16):3295-301. PubMed.

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