title: Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans.
abstract: Characterisation of the interactions between susceptibility loci (epistasis) is central to a full understanding of the genetic aetiology and the molecular pathology of complex diseases. We have examined, in British and French pedigrees, evidence for epistasis between the type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 using two complementary linkage-based approaches. Joint two-locus linkage analysis of 1q and 10q in British pedigrees provided significant evidence for interaction (P < or = 0.003) when comparing a general epistasis model with multiplicative or additive-effects-only models. Conditional linkage analysis (which models epistasis as a deviation from multiplicativity only) confirmed these findings, with significant LOD score increases at the 1q (P = 0.0002) and 10q (P = 0.0023) loci. These analyses provided sizeable reductions in the 1-LOD support intervals for both loci. Analyses of the British and French pedigrees together yielded comparable, but not enhanced, findings, with significant (P < or = 0.003) evidence for epistasis in joint two-locus linkage analysis, and during conditional linkage analysis significant increases in linkage evidence at the 1q (P = 0.0002) and 10q (P = 0.0036) loci. Our findings of epistasis nevertheless substantiate the evidence for genuine genetic effects at both loci, facilitate endeavours to fine-map these loci in population samples, and support further examination of this interaction at the nucleotide level by providing a robust prior hypothesis.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Wiltshire
authors.forename: J T
authors.initials: JT
authors.lastname: Bell
authors.forename: C J
authors.initials: CJ
authors.lastname: Groves
authors.forename: C
authors.initials: C
authors.lastname: Dina
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.forename: G A
authors.initials: GA
authors.lastname: Hitman
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: M
authors.initials: M
authors.lastname: Farrall
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D002878:Chromosomes, Human, Pair 1; D002879:Chromosomes, Human, Pair 10; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004843:Epistasis, Genetic; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D010375:Pedigree; D044465:White People / Q000235:genetics*