RT Journal Article
SR Electronic
T1 Interaction between variants in <em>CLU</em> and <em>MS4A4E</em> modulates Alzheimer’s disease risk
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 028951
DO 10.1101/028951
A1 Mark T. W. Ebbert
A1 Kevin L. Boehme
A1 Mark E. Wadsworth
A1 Lyndsay A. Staley
A1 for the Alzheimer’s Disease Neuroimaging Initiative
A1 Alzheimer’s Disease Genetics Consortium
A1 Shubhabrata Mukherjee
A1 Paul K. Crane
A1 Perry G. Ridge
A1 John S. K. Kauwe
YR 2015
UL http://biorxiv.org/content/early/2015/10/13/028951.abstract
AB 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.METHODS: We tested interactions using 3837 cases and 4145 controls from ADGC using meta-and permutation analyses. We repeated meta-analyses stratified by APOEε4 status, estimated combined 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 APOEε4 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, with APOEε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer’s disease locus except APOEε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer’s disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.