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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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Hum. Mol. Genet. 18, 347-357
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IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells.
S. Liu, H. Wang, Y. Jin, R. Podolsky, M. P. L. Reddy, J. Pedersen, B. Bode, J. Reed, D. Steed, S. Anderson, et al. (2009)
Hum. Mol. Genet. 18, 358-365
   Abstract »    Full Text »    PDF »
Gene-Environment Interaction in Genome-Wide Association Studies.
C. E. Murcray, J. P. Lewinger, and W. J. Gauderman (2009)
Am. J. Epidemiol. 169, 219-226
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Stem Cells Use Distinct Self-renewal Programs at Different Ages.
B.P. Levi and S.J. Morrison (2009)
Cold Spring Harb Symp Quant Biol
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From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene.
Y. Wang, J. R. O'Connell, P. F. McArdle, J. B. Wade, S. E. Dorff, S. J. Shah, X. Shi, L. Pan, E. Rampersaud, H. Shen, et al. (2009)
PNAS 106, 226-231
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Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice.
Z. Su, X. Wang, S.-W. Tsaih, A. Zhang, A. Cox, S. Sheehan, and B. Paigen (2009)
J. Lipid Res. 50, 116-125
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Targeting Hepatic Glucokinase in Type 2 Diabetes: Weighing the Benefits and Risks.
L. Agius (2009)
Diabetes 58, 18-20
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Common Type 2 Diabetes Risk Gene Variants Associate with Gestational Diabetes.
J. Lauenborg, N. Grarup, P. Damm, K. Borch-Johnsen, T. Jorgensen, O. Pedersen, and T. Hansen (2009)
J. Clin. Endocrinol. Metab. 94, 145-150
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Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states.
P. Perez-Martinez, D. Corella, J. Shen, D. K Arnett, N. Yiannakouris, E S. Tai, M. Orho-Melander, K. L Tucker, M. Tsai, R. J Straka, et al. (2009)
Am. J. Clinical Nutrition 89, 391-399
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Prevalence in the United States of Selected Candidate Gene Variants: Third National Health and Nutrition Examination Survey, 1991-1994.
M.-h. Chang, M. L. Lindegren, M. A. Butler, S. J. Chanock, N. F. Dowling, M. Gallagher, R. Moonesinghe, C. A. Moore, R. M. Ned, M. R. Reichler, et al. (2009)
Am. J. Epidemiol. 169, 54-66
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Farp2 and Stk25 Are Candidate Genes for the HDL Cholesterol Locus on Mouse Chromosome 1.
Z. Su, A. Cox, Y. Shen, I. M. Stylianou, and B. Paigen (2009)
Arterioscler Thromb Vasc Biol 29, 107-113
   Abstract »    Full Text »    PDF »
Population-Based Genomewide Genetic Analysis of Common Clinical Chemistry Analytes.
D. I. Chasman, G. Pare, and P. M Ridker (2009)
Clin. Chem. 55, 39-51
   Abstract »    Full Text »    PDF »
Genome-Wide Linkage Scan in Gullah-Speaking African American Families With Type 2 Diabetes: The Sea Islands Genetic African American Registry (Project SuGAR).
M. M. Sale, L. Lu, I. J. Spruill, J. K. Fernandes, K. H. Lok, J. Divers, C. D. Langefeld, and W. T. Garvey (2009)
Diabetes 58, 260-267
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Genome-Wide Linkage Scan for Genes Influencing Plasma Triglyceride Levels in the Veterans Administration Genetic Epidemiology Study.
D. K. Coletta, J. Schneider, S. L. Hu, T. D. Dyer, S. Puppala, V. S. Farook, R. Arya, D. M. Lehman, J. Blangero, R. A. DeFronzo, et al. (2009)
Diabetes 58, 279-284
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SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap.
A. D. Johnson, R. E. Handsaker, S. L. Pulit, M. M. Nizzari, C. J. O'Donnell, and P. I. W. de Bakker (2008)
Bioinformatics 24, 2938-2939
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American College of Endocrinology Pre-Diabetes Consensus Conference: Part Three.
Z. T. Bloomgarden (2008)
Diabetes Care 31, 2404-2409
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The Genetics of Type 2 Diabetes: A Realistic Appraisal in 2008.
J. C. Florez (2008)
J. Clin. Endocrinol. Metab. 93, 4633-4642
   Abstract »    Full Text »    PDF »
The complex genetics of multiple sclerosis: pitfalls and prospects.
S. Sawcer (2008)
Brain 131, 3118-3131
   Abstract »    Full Text »    PDF »
Role of the ENPP1 K121Q Polymorphism in Glucose Homeostasis.
R. Baratta, P. Rossetti, S. Prudente, F. Barbetti, D. Sudano, A. Nigro, M. G. Farina, F. Pellegrini, V. Trischitta, and L. Frittitta (2008)
Diabetes 57, 3360-3364
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An Ancient Evolutionary Origin of Genes Associated with Human Genetic Diseases.
T. Domazet-Loso and D. Tautz (2008)
Mol. Biol. Evol. 25, 2699-2707
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Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes.
A. Doria, J. Wojcik, R. Xu, E. V. Gervino, T. H. Hauser, M. T. Johnstone, D. Nolan, F. B. Hu, and J. H. Warram (2008)
JAMA 300, 2389-2397
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Genotype Score in Addition to Common Risk Factors for Prediction of Type 2 Diabetes.
J. B. Meigs, P. Shrader, L. M. Sullivan, J. B. McAteer, C. S. Fox, J. Dupuis, A. K. Manning, J. C. Florez, P. W.F. Wilson, R. B. D'Agostino Sr., et al. (2008)
N. Engl. J. Med. 359, 2208-2219
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Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes.
V. Lyssenko, A. Jonsson, P. Almgren, N. Pulizzi, B. Isomaa, T. Tuomi, G. Berglund, D. Altshuler, P. Nilsson, and L. Groop (2008)
N. Engl. J. Med. 359, 2220-2232
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Biophysical Characterization of the Interaction between Hepatic Glucokinase and Its Regulatory Protein: IMPACT OF PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTORS.
O. Anderka, J. Boyken, U. Aschenbach, A. Batzer, O. Boscheinen, and D. Schmoll (2008)
J. Biol. Chem. 283, 31333-31340
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