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

Robert Sladek, Ghislain Rocheleau, Johan Rung, Christian Dina, Lishuang Shen, David Serre, Philippe Boutin, Daniel Vincent, Alexandre Belisle, Samy Hadjadj, Beverley Balkau, Barbara Heude, Guillaume Charpentier, Thomas J. Hudson, Alexandre Montpetit, Alexey V. Pshezhetsky, Marc Prentki, Barry I. Posner, David J. Balding, David Meyre, Constantin Polychronakos () and Philippe Froguel
Additional contact information
Robert Sladek: Departments of Human Genetics,
Ghislain Rocheleau: Departments of Human Genetics,
Johan Rung: McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
Christian Dina: CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France
Lishuang Shen: Departments of Human Genetics,
David Serre: Departments of Human Genetics,
Philippe Boutin: CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France
Daniel Vincent: McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
Alexandre Belisle: McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
Samy Hadjadj: Endocrinology and Diabetology, University Hospital, Poitiers 86021 Cedex, France
Beverley Balkau: INSERM U780-IFR69, Villejuif 94807, France
Barbara Heude: INSERM U780-IFR69, Villejuif 94807, France
Guillaume Charpentier: Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes 91100, France
Thomas J. Hudson: McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
Alexandre Montpetit: McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
Alexey V. Pshezhetsky: Montreal Diabetes Research Center, Montreal H2L 4M1, Canada
Marc Prentki: Montreal Diabetes Research Center, Montreal H2L 4M1, Canada
Barry I. Posner: Medicine and,
David J. Balding: Imperial College, St Mary’s Campus, Norfolk Place, London W2 1PG, UK
David Meyre: CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France
Constantin Polychronakos: Departments of Human Genetics,
Philippe Froguel: CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France

Nature, 2007, vol. 445, issue 7130, 881-885

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05616

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