Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Issue 2 (5th October 2015) - Ebbert, Mark T.W.
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.