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

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


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Alzheimer Disease / genetics*
  • Apolipoprotein E4 / genetics*
  • Clusterin / genetics*
  • Epistasis, Genetic*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Risk Factors
  • Sialic Acid Binding Ig-like Lectin 3 / genetics*


  • Apolipoprotein E4
  • CD33 protein, human
  • CLU protein, human
  • Clusterin
  • MS4A4E protein, human
  • Membrane Proteins
  • Sialic Acid Binding Ig-like Lectin 3

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