title: 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 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.
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.forename: Ghislain
authors.initials: G
authors.lastname: Rocheleau
authors.forename: Johan
authors.initials: J
authors.lastname: Rung
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Lishuang
authors.initials: L
authors.lastname: Shen
authors.forename: David
authors.initials: D
authors.lastname: Serre
authors.forename: Philippe
authors.initials: P
authors.lastname: Boutin
authors.forename: Daniel
authors.initials: D
authors.lastname: Vincent
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belisle
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Barbara
authors.initials: B
authors.lastname: Heude
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Barry I
authors.initials: BI
authors.lastname: Posner
authors.forename: David J
authors.initials: DJ
authors.lastname: Balding
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Constantin
authors.initials: C
authors.lastname: Polychronakos
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D015810:Linkage Disequilibrium; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8