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.
Highlights
Alzheimer’s disease (AD, MIM 104300) is by far the most common form of dementia in the elderly
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 earlyonset, high-penetrant disease risk, and the APOE e4 allele, which increases risk of late-onset disease
We show that variants in CUGBP2 on chromosome 10p, along with nearby variants, are associated with AD in those highest-risk APOE e4 homozygotes
Summary
Alzheimer’s disease (AD, MIM 104300) is by far the most common form of dementia in the elderly. Late onset Alzheimer’s disease (LOAD), defined by the onset of symptoms after age 60 years, has annual incidence rates increasing from 1% at 65–70 years to 6–8% at 85 years and older [1]. While the underlying causes of LOAD are still unknown, there is ample evidence for genetic factors affecting risk, including high estimated heritability of LOAD (58–79%) [3], and evidence from both twin [4,5] and family studies [6,7,8,9]. A small number of genes have been identified in which variation contributes to Alzheimer’s disease risk. In contrast to the success in familial EOAD, only one gene, APOE, is an unequivocally established ‘‘susceptibility’’ gene for LOAD [16], with the e4 allele associated with increased risk in a dose-dependent manner and the e2 allele with decreased risk [17]. This, coupled with results of oligogenic segregation analyses supporting the presence of at least 4–6 additional major genes [21,22], suggests that additional risk loci remain to be discovered
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
