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Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes

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

Abbreviations: CEPH, Centre d’Etude du Polymorphisme Humain; LD, linkage disequilibrium; MODY, maturity-onset diabetes of the young; SNP, single nucleotide polymorphism

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 HNF4 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.

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