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

Abstract

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 β-cells, and two linkage disequilibrium blocks that contain genes potentially involved in β-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.

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Figure 1: Graphical summary of stage 1 association results.
Figure 2: Pairwise linkage disequilibrium diagrams for four novel T2DM-associated loci.

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Acknowledgements

This work was funded by Genome Canada, Génome Québec, and the Canada Foundation for Innovation. Cohort recruitment was supported by the Association Française des Diabétiques, INSERM, CNAMTS, Centre Hospitalier Universitaire Poitiers, La Fondation de France and industrial partners. We thank all individuals who participated as cases or controls in this study. C. Petit, J-P. Riveline and S. Franc were instrumental in recruitment and S. Brunet, F. Bacot, R. Frechette, V. Catudal, M. Deweirder, F. Allegaert, P. Laflamme, P. Lepage, W. Astle, M. Leboeuf and S. Leroux provided technical assistance. K. Shazand and N. Foisset provided organizational guidance. Large-scale computations were made possible by the CLUMEQ supercomputer facility.

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Correspondence to Constantin Polychronakos.

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This file contains Supplementary Notes with additional references, Supplementary Tables S1-S8 and Supplementary Figures S1-S5. (PDF 560 kb)

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Sladek, R., Rocheleau, G., Rung, J. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007). https://doi.org/10.1038/nature05616

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