Gastric Breast Cancer Network Center

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels

Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research: * Richa Saxena,1,2,3,4,5,6 Benjamin F. Voight,1,2,3,5 Valeriya Lyssenko,7 Noël P. Burtt,1 Paul I. W. de Bakker,1,2,3,4,5,6 Hong Chen,8 Jeffrey J. Roix,8 Sekar Kathiresan,1,3,5 Joel N. Hirschhorn,1,6,9,10,11 Mark J. Daly,1,2,3,5 Thomas E. Hughes,8 Leif Groop,7,12 David Altshuler,1,2,3,4,5,6 Peter Almgren,7 Jose C. Florez,1,2,3,4,5,6 Joanne Meyer,8 Kristin Ardlie,1 Kristina Bengtsson Boström,13 Bo Isomaa,14,15 Guillaume Lettre,1,6,9,10,11 Ulf Lindblad,16 Helen N. Lyon,1,6,9,10,11 Olle Melander,7 Christopher Newton-Cheh,1,2,3,5 Peter Nilsson,17 Marju Orho-Melander,7 Lennart Råstam,16 Elizabeth K. Speliotes,1,3,6,9,10,11 Marja-Riitta Taskinen,12 Tiinamaija Tuomi,12,15 Candace Guiducci,1 Anna Berglund,7 Joyce Carlson,18 Lauren Gianniny,1 Rachel Hackett,1 Liselotte Hall,18 Johan Holmkvist,7 Esa Laurila,7 Marketa Sjögren,7 Maria Sterner,18 Aarti Surti,1 Margareta Svensson,7 Malin Svensson,7 Ryan Tewhey,1 Brendan Blumenstiel,1 Melissa Parkin,1 Matthew DeFelice,1 Rachel Barry,1 Wendy Brodeur,1 Jody Camarata,1 Nancy Chia,1 Mary Fava,1 John Gibbons,1 Bob Handsaker,1 Claire Healy,1 Kieu Nguyen,1 Casey Gates,1 Carrie Sougnez,1 Diane Gage,1 Marcia Nizzari,1 Stacey B. Gabriel,1 Gung-Wei Chirn,8 Qicheng Ma,8 Hemang Parikh,7 Delwood Richardson,8 Darrell Ricke,8 Shaun Purcell1,2,19

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D—in a noncoding region near CDKN2A and CDKN2B , in an intron of IGF2BP2 , and an intron of CDKAL1 —and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.

1 Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
3 Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
4 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
5 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
6 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
7 Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, Malmö, Sweden.
8 Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
9 Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
10 Division of Endocrinology, Children's Hospital, Boston, MA 02115, USA.
11 Division of Genetics, Children's Hospital, Boston, MA 02115, USA.
12 Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
13 Skaraborg Institute, Skövde, Sweden.
14 Malmska Municipal Health Center and Hospital, Jakobstad, Finland.
15 Folkhälsan Research Center, Helsinki, Finland.
16 Department of Clinical Sciences, Community Medicine Research Unit, University Hospital Malmö, Lund University, Malmö, Sweden.
17 Department of Clinical Sciences, Medicine Research Unit, University Hospital Malmö, Lund University, Malmö, Sweden.
18 Clinical Chemistry, University Hospital Malmö, Lund University, Malmö, Sweden.
19 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.

All authors with their contributions and affiliations appear at the end of this paper.

* To whom correspondence should be addressed: David Altshuler, Leif Groop, Thomas E. Hughes. E-mail: altshuler@molbio.mgh.harvard.edu (D.A.); leif.groop@med.lu.se (L.G.); thomase.hughes@novartis.com (T.E.H.)