ARTICLESA genome-wide association studyidentifies novel risk loci for type 2 diabetesRobert Sladek1,2,4, Ghislain Rocheleau1*, Johan Rung4*, Christian Dina5*, Lishuang Shen1, David Serre1,Philippe Boutin5, Daniel Vincent4, Alexandre Belisle4, Samy Hadjadj6, Beverley Balkau7, Barbara Heude7,Guillaume Charpentier8, Thomas J. Hudson4,9, Alexandre Montpetit4, Alexey V. Pshezhetsky10, Marc Prentki10,11,Barry I. Posner2,12, David J. Balding13, David Meyre5, Constantin Polychronakos1,3& Philippe Froguel5,14Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most ofwhich were hitherto unknown. A systematic search for these variants was recently made possible by the development ofhigh-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935single-nucleotide polymorphisms in a French case–control cohort. Markers with the most significant difference in genotypefrequencies between cases of type 2 diabetes and co ntrols were fast-tracked for testing in a second cohort. This identifiedfour loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively ininsulin-producing b-cells, and two linkage disequilibrium blocks that contain genes potentially involved in b-celldevelopment or function (IDE–KIF11–HHEX and EXT2–ALX4). These associations explain a substantial portion of disease riskand constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.The rapidly increasing prevalence of type 2 diabetes mellitus (T2DM) isthought to be due to environmental factors, such as increased availabil-ity of food and decreased opportunity and motivation for physicalactivity, acting on genetically susceptible individuals. The heritabilityof T2DM is one of the best established among common diseases and,consequently, genetic risk factors for T2DM have been the subject ofintense research1. Although the genetic causes of many monogenicforms of diabetes (maturity onset diabetes in the young, neonatal mito-chondrial and other syndromic types of diabetes mellitus) have beenelucidated, few variants leading to common T2DM have been clearlyidentified and individually confer only a small risk (odds ratio < 1.1–1.25) of developing T2DM1. Linkage studies have reported manyT2DM-linked chromosomal regions and have identified putative, cau-sative genetic variants in CAPN10 (ref. 2), ENPP1 (ref. 3), HNF4A (refs4, 5) and ACDC (also called ADIPOQ)6. In parallel, candidate-genestudies havereported many T2DM-associated loci, with coding variantsin the nuclear receptor PPARG (P12A)7and the potassium channelKCNJ11 (E23K)8being among the very few that have been convincinglyreplicated. The strongest known (odds ratio < 1.7) T2DM association9was recently mapped to the transcription factor TCF7L2 and has beenconsistently replicated in multiple populations10–20.Subjects and study designThe recent availability of high-density genotyping arrays, which com-bine the power of association studies with the systematic nature of agenome-wide search, led us to undertake a two-stage, genome-wideassociation study to identify additional T2DM susceptibility loci(Supplementary Fig. 1). In the first stage of this study, we obtainedgenotypes for 392,935 single-nucleotide polymorphisms (SNPs) in1,363 T2DM cases and controls (Supplementary Table 1). In order toenrich for risk alleles21, the diabetic subjects studied in stage 1 wereselected to have at least one affected first degree relative and age atonset under 45 yr (excluding patients with maturity onset diabetes inthe young). Furthermore, in order to decrease phenotypic hetero-geneity and to enrich for variants determining insulin resistance andb-cell dysfunction through mechanisms other than severe obesity, weinitially studied diabetic patients with a body mass index (BMI),30 kg m22. Control subjects were selected to have fasting bloodglucose ,5.7 mmol l21in DESIR, a large prospective cohort for thestudy of insulin resistance in French subjects22.Genotypes for each study subject were obtained using two plat-forms: Illumina Infinium Human1 BeadArrays, which assay 109,365SNPs chosen using a gene-centred design; and Human Hap300BeadArrays, which assay 317,503 SNPs chosen to tag haplotypeblocks identified by the Phase I HapMap23. Of the 409,927 markersthat passed quality control (Supplementary Tables 2 and 3), geno-types were obtained for an average of 99.2% (Human1) and 99.4%(Hap300) of markers for each subject with a reproducibility of.99.9% (both platforms). Forty-three subjects were removed fromanalysis because of evidence of intercontinental admixture (Sup-plementary Fig. 3) and an additional four because their genotype-determined gender disagreed with clinical records. In total, T2DMassociation was tested for 100,764 (Human1) and 309,163 (Hap300)SNPs representing 392,935 unique loci (Fig. 1). Because of unequalmale/female ratios in our cases and controls, we analysed the 12,666sex-chromosome SNPs separately for each gender.*These authors contributed equally to this work.1Departments of Human Genetics,2Medicine and3Pediatrics, Faculty of Medicine, McGill University, Montreal H3H 1P3, Canada.4McGill University and Genome Quebec InnovationCentre, Montreal H3A 1A4, Canada.5CNRS 8090-Institute of Biology, Pasteur Institute, Lille 59019 Cedex, France.6Endocrinology and Diabetology, University Hospital, Poitiers86021 Cedex, France.7INSERM U780-IFR69, Villejuif 94807, France.8Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes 91100, France.9OntarioInstitute for Cancer Research, Toronto M5G 1L7, Canada.10Montreal Diabetes Research Center, Montreal H2L 4M1, Canada.11Molecular Nutrition Unit and the Department ofNutrition, University of Montreal and the Centre Hospitalier de l’Universite´de Montre´al, Montreal H3C 3J7, Canada.12Polypeptide Hormone Laboratory and Department of Anatomyand Cell Biology, Montreal H3A 2B2, Canada.13Department of Epidemiology & Public Health, Imperial College, St Mary’s Campus, Norfolk Place, London W2 1PG, UK.14Section ofGenomic Medicine, Imperial College London W12 0NN, and Hammersmith Hospital, Du Cane Road, London W12 0HS, UK.Vol 445|22 February 2007|doi:10.1038/nature05616881Nature