title: Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease.
abstract: Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region.
authors.affiliation: Human Genetics, School of Molecular Medical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Bullock
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.forename: Mario
authors.initials: M
authors.lastname: Cortina-Borja
authors.forename: James C
authors.initials: JC
authors.lastname: Turton
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
authors.forename: Carla A
authors.initials: CA
authors.lastname: Ibrahim-Verbaas
authors.forename: Maaike
authors.initials: M
authors.lastname: Schuur
authors.forename: Monique M
authors.initials: MM
authors.lastname: Breteler
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Rachel
authors.initials: R
authors.lastname: Barber
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Naomi
authors.initials: N
authors.lastname: Hammond
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mateo
authors.forename: Donald R
authors.initials: DR
authors.lastname: Warden
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lehmann
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.forename: Kristelle
authors.initials: K
authors.lastname: Brown
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Wilcock
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Lehmann
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D002874:Chromosome Mapping; D004843:Epistasis, Genetic / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing / Q000706:statistics & numerical data; D005982:Glutathione Transferase / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D016547:Kinesins / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C470243:KIF11 protein, human; D014157:Transcription Factors; C483009:GSTM3 protein, human; D005982:Glutathione Transferase; D007339:Insulysin; D016547:Kinesins