Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes Wendy Winckler 1 2 3 , Michael N. Weedon 4 , Robert R. Graham 1 2 3 , Steven A. McCarroll 1 2 3 , Shaun Purcell 3 , Peter Almgren 5 , Tiinamaija Tuomi 6 7 , Daniel Gaudet 8 , Kristina Bengtsson Boström 9 , Mark Walker 10 , Graham Hitman 11 , Andrew T. Hattersley 4 , Mark I. McCarthy 12 , Kristin G. Ardlie 13 , Joel N. Hirschhorn 2 3 14 , Mark J. Daly 3 , Timothy M. Frayling 4 , Leif Groop 5 and David Altshuler 1 2 3 15 16 1 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Genetics, Harvard Medical School, Boston, Massachusetts 3 Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 4 Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K 5 Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden 6 Department of Medicine, Helsinki University Central Hospital 7 Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland 8 University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada 9 Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden 10 Department of Medicine, School of Medicine, University of Newcastle, Newcastle Upon Tyne, U.K 11 Department of Diabetes and Metabolic Medicine, Barts and The London, Queen Mary School of Medicine and Dentistry, University of London, London, U.K 12 Department of Endocrinology and Metabolism, Diabetes Research Laboratories, Oxford Centre for Diabetes, Churchill Hospital, Oxford, U.K 13 Genomics Collaborative, Cambridge, Massachusetts 14 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts 15 Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 16 Department of Medicine, Harvard Medical School, Boston, Massachusetts Address correspondence and reprint requests to David Altshuler, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142. E-mail: altshuler{at}molbio.mgh.harvard.edu Abstract An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4–MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value <0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values <0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value <10 −6 in >15,000 samples. We combined these results with our previous studies on HNF4α and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes. CEPH, Centre d’Etude du Polymorphisme Humain LD, linkage disequilibrium MODY, maturity-onset diabetes of the young SNP, single nucleotide polymorphism Footnotes L.G. has been a consultant for and served on the advisory boards for Aventis-Sanofi, Bristol Myers Squibb, GKS, Kowa, and Roche. D.A. is a paid consultant and member of the scientific advisory board of Genomics Collaborative. L.G. and D.A. jointly supervised the project. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0202 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted December 4, 2006. Received February 10, 2006. DIABETES