1. Departments of Human Genetics,
2. Medicine and,
3. Pediatrics, Faculty of Medicine, McGill University, Montreal H3H 1P3, Canada
4. McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
5. CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France
6. Endocrinology and Diabetology, University Hospital, Poitiers 86021 Cedex, France
7. INSERM U780-IFR69, Villejuif 94807, France
8. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes 91100, France
9. Ontario Institute for Cancer Research, Toronto M5G 1L7, Canada
10. Montreal Diabetes Research Center, Montreal H2L 4M1, Canada
11. Molecular Nutrition Unit and the Department of Nutrition, University of Montreal and the Centre Hospitalier de l'Université de Montréal, Montreal H3C 3J7, Canada
12. Polypeptide Hormone Laboratory and Department of Anatomy and Cell Biology, Montreal H3A 2B2, Canada
13. Department of Epidemiology & Public Health, Imperial College, St Mary's Campus, Norfolk Place, London W2 1PG, UK
14. Section of Genomic Medicine, Imperial College London W12 0NN, and Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
15. These authors contributed equally to this work.

Correspondence to: Constantin Polychronakos^1,3 Correspondence and requests for materials should be addressed to C.P. (Email: Constantin.Polychronakos@McGill.ca).

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

1. Departments of Human Genetics,
2. Medicine and,
3. Pediatrics, Faculty of Medicine, McGill University, Montreal H3H 1P3, Canada
4. McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
5. CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France
6. Endocrinology and Diabetology, University Hospital, Poitiers 86021 Cedex, France
7. INSERM U780-IFR69, Villejuif 94807, France
8. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes 91100, France
9. Ontario Institute for Cancer Research, Toronto M5G 1L7, Canada
10. Montreal Diabetes Research Center, Montreal H2L 4M1, Canada
11. Molecular Nutrition Unit and the Department of Nutrition, University of Montreal and the Centre Hospitalier de l'Université de Montréal, Montreal H3C 3J7, Canada
12. Polypeptide Hormone Laboratory and Department of Anatomy and Cell Biology, Montreal H3A 2B2, Canada
13. Department of Epidemiology & Public Health, Imperial College, St Mary's Campus, Norfolk Place, London W2 1PG, UK
14. Section of Genomic Medicine, Imperial College London W12 0NN, and Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
15. These authors contributed equally to this work.

Correspondence to: Constantin Polychronakos^1,3 Correspondence and requests for materials should be addressed to C.P. (Email: Constantin.Polychronakos@McGill.ca).

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