Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE

Abstract

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10⁻⁸¹), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10⁻⁸). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies. Genetic factors are well-established to play a role in risk of Alzheimer's disease (AD). However, it has been difficult to find genes that are involved in AD susceptibility, other than a small number of genes that play a role in early-onset, high-penetrant disease risk, and the APOE ε4 allele, which increases risk of late-onset disease. Here we use a European-American family-based sample to examine the role of common genetic variants on late-onset AD. We show that variants in CUGBP2 on chromosome 10p, along with nearby variants, are associated with AD in those highest-risk APOE ε4 homozygotes. We have replicated this interaction in an independent sample. CUGBP2 has one isoform that is expressed predominantly in neurons, and identification of such a new risk locus is important because of the severity of AD. We also provide support for recently proposed associated variants (BIN1, CLU, and partly CR1) and show that there are markers throughout the genome that are correlated with APOE. This emphasizes the need to adjust for APOE for such markers to avoid false associations and suggests that there may be confounding for other diseases with similar strong risk loci.