Dataset Information

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

ABSTRACT: INTRODUCTION:Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study. METHODS:We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ?4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants. RESULTS:Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ?4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. DISCUSSION:We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ?4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ?4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.

SUBMITTER: Ebbert MTW

PROVIDER: S-EPMC4744542 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

Ebbert Mark T W MTW Boehme Kevin L KL Wadsworth Mark E ME Staley Lyndsay A LA Mukherjee Shubhabrata S Crane Paul K PK Ridge Perry G PG Kauwe John S K JSK

Alzheimer's & dementia : the journal of the Alzheimer's Association 20151009 2

<h4>Introduction</h4>Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study.<h4>Methods</h4>We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) a ...[more]

PMID: 26449541

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Project description: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 ?4 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.

Dataset Information

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

Publications

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

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