Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans.
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.
Wiltshire
S
S
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Bell
J T
JT
Groves
C J
CJ
Dina
C
C
Hattersley
A T
AT
Frayling
T M
TM
Walker
M
M
Hitman
G A
GA
Vaxillaire
M
M
Farrall
M
M
Froguel
P
P
McCarthy
M I
MI
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*