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

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. [ABSTRACT FROM AUTHOR]