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
- Christopher J. Groves1,
- Eleftheria Zeggini1,2,
- Jayne Minton3,
- Timothy M. Frayling3,
- Michael N. Weedon3,
- Nigel W. Rayner1,2,
- Graham A. Hitman4,
- Mark Walker5,
- Steven Wiltshire2,
- Andrew T. Hattersley3 and
- Mark I. McCarthy1,2
- 1Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, U.K
- 2Wellcome Trust Centre for Human Genetics, Headington, Oxford, U.K
- 3Department of Diabetes Research and Vascular Medicine, Peninsula Medical School, Exeter, U.K
- 4Department of Diabetes and Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, London, U.K
- 5Department of Medicine, School of Medicine, Newcastle University, Newcastle upon Tyne, U.K
- Address correspondence and reprint requests to Prof. Mark McCarthy, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail:
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 × 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 × 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 ∼16%. The overall evidence for association for these variants (P = 4.4 × 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.
- Received March 17, 2006.
- Accepted May 30, 2006.