title: APOE and MS4A6A interact with GnRH signaling in Alzheimer's disease: Enrichment of epistatic effects.
abstract: BACKGROUND
  It is unknown if risk loci, identified by genome-wide association studies of late-onset Alzheimer's disease (LOAD), are linked to common molecular mechanisms through epistatic effects.
  
  
  METHODS
  We performed genome-wide interaction studies of five risk variants for LOAD followed by enrichment analyses to find if there are pathways that simultaneously interact with more than one variant. This novel approach was applied to four independent cohorts (5393 cases and 3746 controls).
  
  
  RESULTS
  We found enrichment of epistasis in gonadotropin-releasing hormone signaling with risk single-nucleotide polymorphisms in APOE and MS4A6A (P value = 3.7 × 10-5, P value = 5.6 × 10-6); vascular smooth muscle contraction pathway was also enriched in epistasis with these loci (P value = 9.6 × 10-5, P value = 2.4 × 10-7). MS4A6A risk variant also interacted with dilated cardiomyopathy pathway (P value = 3.1 × 10-7).
  
  
  CONCLUSIONS
  In addition to APOE, MS4A6A polymorphisms should be considered in hormone trials targeting gonadotropins. Interactions of risk variants with neurovascular pathways may also be important in LOAD pathology.
authors.affiliation: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. Electronic address: acaceres@creal.cat.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cáceres
authors.affiliation: CAPES Foundation, Ministry of Education of Brazil, Brasilia, Brazil.
authors.forename: José E
authors.initials: JE
authors.lastname: Vargas
authors.affiliation: ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Mathematics, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Juan R
authors.initials: JR
authors.lastname: González
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D003198:Computer Simulation; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C574492:MS4A6A protein, human; D008565:Membrane Proteins; D007987:Gonadotropin-Releasing Hormone
keywords: APOE; Alzheimer's disease; Epistasis; GWAS; GnRH signaling; Gonadotropin; MS4A6A; PICALM; Pathway analysis; SNP