title: Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Mark T W
authors.initials: MTW
authors.lastname: Ebbert
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Boehme
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wadsworth
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Lyndsay A
authors.initials: LA
authors.lastname: Staley
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA. Electronic address: kauwe@byu.edu.
authors.forename: John S K
authors.initials: JSK
authors.lastname: Kauwe
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D051152:Clusterin / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D012307:Risk Factors; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; C571163:CD33 protein, human; C495242:CLU protein, human; D051152:Clusterin; C436715:MS4A4E protein, human; D008565:Membrane Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3
keywords: ADGC; ADNI; Alzheimer's disease; CD33; CLU; Epistasis; MS4A4E; Meta-analysis