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Alzheimers Dement. 2016 Feb;12(2):121-129. doi: 10.1016/j.jalz.2015.08.163. Epub 2015 Oct 9.

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

Author information

1
Department of Biology, Brigham Young University, Provo, UT, USA.
2
Department of Medicine, University of Washington, Seattle, WA, USA.
3
Department of Biology, Brigham Young University, Provo, UT, USA. Electronic address: kauwe@byu.edu.

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) ε4 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 ε4 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 ε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.

KEYWORDS:

ADGC; ADNI; Alzheimer's disease; CD33; CLU; Epistasis; MS4A4E; Meta-analysis

PMID:
26449541
PMCID:
PMC4744542
DOI:
10.1016/j.jalz.2015.08.163
[Indexed for MEDLINE]
Free PMC Article

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