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

被引：16

作者：

Ebbert, Mark T. W. ^{[1
]}

Boehme, Kevin L. ^{[1
]}

Wadsworth, Mark E. ^{[1
]}

Staley, Lyndsay A. ^{[1
]}

Mukherjee, Shubhabrata ^{[2
]}

Crane, Paul K. ^{[2
]}

Ridge, Perry G. ^{[1
]}

Kauwe, John S. K. ^{[1
]}

机构：

[1] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA

[2] Univ Washington, Dept Med, Seattle, WA 98195 USA

来源：

ALZHEIMERS & DEMENTIA | 2016年 / 12卷 / 02期

基金：

英国医学研究理事会; 英国惠康基金; 加拿大健康研究院; 美国国家卫生研究院;

关键词：

Alzheimer's disease; Epistasis; MS4A4E; CLU; CD33; Meta-analysis; ADGC; ADNI; SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; PERSONAL GENOMES; COMMON VARIANTS; EXACT TESTS; ONSET AGE; ASSOCIATION; CD33; METAANALYSIS; CD2AP;

D O I：

10.1016/j.jalz.2015.08.163

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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) epsilon 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 epsilon 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 epsilon 4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE epsilon 4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

引用

页码：121 / 129

页数：9

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