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

James M Bullock, Christopher Medway, Mario Cortina-Borja, James C Turton, Jonathan A Prince, Carla A Ibrahim-Verbaas, Maaike Schuur, Monique M Breteler, Cornelia M van Duijn, Patrick G Kehoe, Rachel Barber, Eliecer Coto, Victoria Alvarez, Panos Deloukas, Naomi Hammond, Onofre Combarros, Ignacio Mateo, Donald R Warden, Michael G Lehmann, Olivia BelbinKristelle Brown, Gordon K Wilcock, Reinhard Heun, Heike Kölsch, A David Smith, Donald J Lehmann, Kevin Morgan*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

22 Citations (Scopus)

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 epsilon 4 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 epsilon 4 allele of apolipoprotein E genotype, and geographic region. (C) 2013 Elsevier Inc. All rights reserved.

Original languageEnglish
Article numberARTN 1309.e1
Pages (from-to)1309.e1-7
Number of pages7
JournalNeurobiology of Aging
Volume34
Issue number4
DOIs
Publication statusPublished - Apr 2013

Bibliographical note

Copyright © 2013 Elsevier Inc. All rights reserved.

Keywords

  • Epistasis
  • Alzheimer's risk
  • GSTM3
  • IDE locus
  • GENOME-WIDE ASSOCIATION
  • DEGRADING ENZYME GENE
  • IDENTIFIES VARIANTS
  • INSULIN
  • POLYMORPHISMS
  • REPLICATION
  • ANNOTATION
  • EXPRESSION
  • DIAGNOSIS
  • PROTEIN

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