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

Naturevolume 445, pages881–885 (2007)Cite this article

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 theTCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporterSLC30A8, 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 andEXT2–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.

Author information

Author notes

  1. Ghislain Rocheleau, Johan Rung and Christian Dina: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Human Genetics,,

    Robert Sladek, Ghislain Rocheleau, Lishuang Shen, David Serre & Constantin Polychronakos

  2. Medicine and,,

    Robert Sladek & Barry I. Posner

  3. Pediatrics, Faculty of Medicine, McGill University, Montreal H3H 1P3, Canada,

    Constantin Polychronakos

  4. McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada,

    Robert Sladek, Johan Rung, Daniel Vincent, Alexandre Belisle, Thomas J. Hudson & Alexandre Montpetit

  5. CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France,

    Christian Dina, Philippe Boutin, David Meyre & Philippe Froguel

  6. Endocrinology and Diabetology, University Hospital, Poitiers 86021 Cedex, France,

    Samy Hadjadj

  7. INSERM U780-IFR69, Villejuif 94807, France,

    Beverley Balkau & Barbara Heude

  8. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes 91100, France,

    Guillaume Charpentier

  9. Ontario Institute for Cancer Research, Toronto M5G 1L7, Canada,

    Thomas J. Hudson

  10. Montreal Diabetes Research Center, Montreal H2L 4M1, Canada,

    Alexey V. Pshezhetsky & Marc Prentki

  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,

    Marc Prentki

  12. Polypeptide Hormone Laboratory and Department of Anatomy and Cell Biology, Montreal H3A 2B2, Canada,

    Barry I. Posner

  13. Department of Epidemiology & Public Health, Imperial College, St Mary’s Campus, Norfolk Place, London W2 1PG, UK,

    David J. Balding

  14. Section of Genomic Medicine, Imperial College London W12 0NN, and Hammersmith Hospital, Du Cane Road, London W12 0HS, UK,

    Philippe Froguel

Authors
  1. Robert Sladek

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  2. Ghislain Rocheleau

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  11. Beverley Balkau

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  13. Guillaume Charpentier

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Correspondence toConstantin 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.Nature445, 881–885 (2007). https://doi.org/10.1038/nature05616

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Editorial Summary

Diabetes in the genes

Overeating and physical inactivity are major causes of type 2 diabetes mellitus, but they affect only genetically susceptible individuals and the genetic basis of the disease is notoriously complex. Recent research has suggested that specific genes may be associated with the risk of developing the disease, however. Now a genome-wide search using high-density genotyping arrays has identified four previously unknown genes as diabetes risk factors, and confirmed a known association with theTCF7L2 gene. Together these five genes may contribute a sizeable fraction of the disease risk in type 2 diabetes, and analysis of their function should clarify the pathogenesis of diabetes and point to new drug targets. In addition, individuals shown to have these mutations could minimize their risk by adjusting diet.

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