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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.

Original publication

DOI

10.1016/j.neurobiolaging.2012.08.010

Type

Journal article

Journal

Neurobiology of aging

Publication Date

04/2013

Volume

34

Pages

1309.e1 - 1309.e7

Addresses

Human Genetics, School of Molecular Medical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.

Keywords

Humans, Alzheimer Disease, Genetic Predisposition to Disease, Kinesin, Insulysin, Glutathione Transferase, Homeodomain Proteins, Transcription Factors, Genetic Markers, Prevalence, Risk Factors, Chromosome Mapping, Epistasis, Genetic, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Europe, Female, Male, Genetic Testing, Genetic Loci