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bioRxiv · 10.1101/028951

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

Mark T. W. Ebbert·Kevin L. Boehme·Mark E. Wadsworth·Lyndsay A. Staley·for the Alzheimer's Disease Neuroimaging Initiativ·Alzheimer's Disease Genetics Consortium·Shubhabrata Mukherjee·Paul K. Crane·Perry G. Ridge·John S. K. Kauwe
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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 dataset for an epistasis study.\n\nMETHODS: We tested interactions using 3837 cases and 4145 controls from ADGC using meta-and permutation analyses. We repeated meta-analyses stratified by APOE{varepsilon}4 status, estimated combined OR and population attributable fraction (cPAF), and explored causal variants.\n\nRESULTS: Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE{varepsilon}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.\n\nDISCUSSION: We replicated the CLU-MS4A4E interaction in a large case-control series, with APOE{varepsilon}4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimers disease locus except APOE{varepsilon}4, APP, and TREM2. We estimated an 8% decrease in Alzheimers disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.

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Mark T. W. Ebbert, Kevin L. Boehme, Mark E. Wadsworth, Lyndsay A. Staley, for the Alzheimer's Disease Neuroimaging Initiativ, Alzheimer's Disease Genetics Consortium, Shubhabrata Mukherjee, Paul K. Crane, Perry G. Ridge, John S. K. Kauwe. 2015-10-13. Interaction between variants in CLU and MS4A4E modulates Alzheimer’s disease risk. https://doi.org/10.1101/028951

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