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Published Online April 26, 2007
Science DOI: 10.1126/science.1142358

Reports

Submitted on March 9, 2007
Accepted on April 20, 2007

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

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

* To whom correspondence should be addressed.
Thomas E. Hughes , E-mail: thomase.hughes{at}novartis.com
Leif Groop , E-mail: leif.groop{at}med.lu.se
David Altshuler , E-mail: altshuler{at}molbio.mgh.harvard.edu

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 1,464 patients with T2D and 1,467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D) we identify and confirm three loci associated with T2D -- in a non-coding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 -- and replicate associations near HHEX and in SLC30A8 found by a recent whole genome association study. We identify and confirm association of a SNP in an intron of glucokinase regulatory protein 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 into the pathogenesis of common diseases.


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