title: Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.
abstract: Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10(-11)). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P = 7 x 10(-5)) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is approximately 16%. The overall evidence for association for these variants (P = 4.4 x 10(-14) combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Jayne
authors.initials: J
authors.lastname: Minton
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Rayner
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Steven
authors.initials: S
authors.lastname: Wiltshire
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D006113:United Kingdom
chemical_list: D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein