A genome-wide association study identifies novel risk loci for type 2 diabetes.

Robert Sladek , Ghislain Rocheleau , Johan Rung , Christian Dina (1) , Lishuang Shen , David Serre , Philippe Boutin (1) , Daniel Vincent (2, 3, 4, 5, 6) , Alexandre Belisle , Samy Hadjadj (7) , Beverley Balkau (8) , Barbara Heude (8) , Guillaume Charpentier (9, 10) , Thomas J Hudson , Alexandre Montpetit , Alexey V Pshezhetsky , Marc Prentki , Barry I Posner , David J Balding , David Meyre (1) , Constantin Polychronakos , Philippe Froguel (1, 11, 12)

1 GMM - Génétique des maladies multifactorielles
2 EPOC - Environnements et Paléoenvironnements OCéaniques
3 ELICO - Ecosystèmes littoraux et côtiers - UMR 8013
4 LOB ARCACHON - Laboratoire d'Océanologie Biologique d'Arcachon
5 Ecosystèmes Littoraux et Cotiers
6 LRCCI - Laboratoire de Recherche sur les capteurs à colloides et l'instrumentation
7 Service d'Endocrinologie et Diabétologie [CHU Poitiers]
8 Recherche en épidémiologie et biostatistique
9 Service de diabétologie
10 Service d'endocrinologie et diabetologie
11 Section of Genomic Medicine
12 Genome Centre

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.

Domaines: Génétique humaine

Robert Sladek, Ghislain Rocheleau, Johan Rung, Christian Dina, Lishuang Shen, et al.. A genome-wide association study identifies novel risk loci for type 2 diabetes.. Nature, 2007, 445 (7130), pp.881-5. ⟨10.1038/nature05616⟩. ⟨hal-00173692⟩