Abstract
ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498
Highlights
The EPHA1 variant was absent in the genotyped Caucasian controls and the BIN1 variant had the same frequency as the Caucasian late onset Alzheimer disease (LOAD) cases
Caucasians For the 12 variants detected in the National Institute on Aging (NIA)-LOAD and Toronto data sets (Table 3), we compared the frequency of SNVs between 330 cases in these data sets and the 33,370 non-Finnish Europeans from Exome Aggregation Consortium (ExAC) using a Fisher exact test
The p.K358R variant in BIN1 was observed in 1.8% of the ExAC database Caucasians, which is similar to the frequency we observed in the cohort of patients here with LOAD
Summary
To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD). The first large-scale genome-wide association studies (GWAS) using common single nucleotide polymorphisms (SNPs) identified CLU, PICALM, CR1, and BIN1 as late onset Alzheimer disease (LOAD) susceptibility. Targeted exome sequencing of large multiplex pedigrees with LOAD identified mutations in APP, PSEN1, and PSEN2,11,12 indicating that rare coding sequence variants even in genes associated with early onset Alzheimer disease (AD) may account for a portion of disease risk in LOAD. Because the majority of loci detected by SNP-based GWAS of LOAD have not been investigated for rare coding sequence variants, we conducted targeted sequencing of the top 8 genetic loci frequently associated with LOAD,[7,8,16,17,18] with the exception of the CD33 locus, which was not well replicated in subsequent large meta-GWAS.[18]
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