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Originally published in Science Express on 26 April 2007
Science 1 June 2007:
Vol. 316. no. 5829, pp. 1331 - 1336
DOI: 10.1126/science.1142358
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Reports

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: *{dagger} 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.

{dagger} 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{at}molbio.mgh.harvard.edu (D.A.); leif.groop{at}med.lu.se (L.G.); thomase.hughes{at}novartis.com (T.E.H.)

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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
   Abstract »    Full Text »    PDF »
An Ancient Evolutionary Origin of Genes Associated with Human Genetic Diseases.
T. Domazet-Loso and D. Tautz (2008)
Mol. Biol. Evol. 25, 2699-2707
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Genetic Mapping in Human Disease.
D. Altshuler, M. J. Daly, and E. S. Lander (2008)
Science 322, 881-888
   Abstract »    Full Text »    PDF »
Association Study of Prostate Cancer Susceptibility Variants with Risks of Invasive Ovarian, Breast, and Colorectal Cancer.
H. Song, T. Koessler, S. Ahmed, S. J. Ramus, S. K. Kjaer, R. A. DiCioccio, E. Wozniak, E. Hogdall, A. S. Whittemore, V. McGuire, et al. (2008)
Cancer Res. 68, 8837-8842
   Abstract »    Full Text »    PDF »
Learning From Molecular Genetics: Novel Insights Arising From the Definition of Genes for Monogenic and Type 2 Diabetes.
M. I. McCarthy and A. T. Hattersley (2008)
Diabetes 57, 2889-2898
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Genes Associated With Risk of Type 2 Diabetes Identified by a Candidate-Wide Association Scan: As a Trickle Becomes a Flood.
S. S. Rich, J. M. Norris, and J. I. Rotter (2008)
Diabetes 57, 2915-2917
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Associations Between Single Nucleotide Polymorphisms on Chromosome 9p21 and Risk of Coronary Heart Disease in Chinese Han Population.
L. Zhou, X. Zhang, M. He, L. Cheng, Y. Chen, F. B. Hu, and T. Wu (2008)
Arterioscler. Thromb. Vasc. Biol. 28, 2085-2089
   Abstract »    Full Text »    PDF »
Common SNPs in HMGCR in Micronesians and Whites Associated With LDL-Cholesterol Levels Affect Alternative Splicing of Exon13.
R. Burkhardt, E. E. Kenny, J. K. Lowe, A. Birkeland, R. Josowitz, M. Noel, J. Salit, J. B. Maller, I. Pe'er, M. J. Daly, et al. (2008)
Arterioscler. Thromb. Vasc. Biol. 28, 2078-2084
   Abstract »    Full Text »    PDF »
Assessing the Combined Impact of 18 Common Genetic Variants of Modest Effect Sizes on Type 2 Diabetes Risk.
H. Lango, the U.K. Type 2 Diabetes Genetics Consortium, C. N.A. Palmer, A. D. Morris, E. Zeggini, A. T. Hattersley, M. I. McCarthy, T. M. Frayling, and M. N. Weedon (2008)
Diabetes 57, 3129-3135
   Abstract »    Full Text »    PDF »
PCLO Variants Are Nominally Associated With Early-Onset Type 2 Diabetes and Insulin Resistance in Pima Indians.
L. Ma, R. L. Hanson, L. N. Que, Y. Guo, S. Kobes, C. Bogardus, and L. J. Baier (2008)
Diabetes 57, 3156-3160
   Abstract »    Full Text »    PDF »
Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits With 222 Candidate Genes.
K. J. Gaulton, C. J. Willer, Y. Li, L. J. Scott, K. N. Conneely, A. U. Jackson, W. L. Duren, P. S. Chines, N. Narisu, L. L. Bonnycastle, et al. (2008)
Diabetes 57, 3136-3144
   Abstract »    Full Text »    PDF »
Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations.
M. Orho-Melander, O. Melander, C. Guiducci, P. Perez-Martinez, D. Corella, C. Roos, R. Tewhey, M. J. Rieder, J. Hall, G. Abecasis, et al. (2008)
Diabetes 57, 3112-3121
   Abstract »    Full Text »    PDF »
Predicting Type 2 Diabetes Based on Polymorphisms From Genome-Wide Association Studies: A Population-Based Study.
M. van Hoek, A. Dehghan, J. C.M. Witteman, C. M. van Duijn, A. G. Uitterlinden, B. A. Oostra, A. Hofman, E. J.G. Sijbrands, and A. C. J.W. Janssens (2008)
Diabetes 57, 3122-3128
   Abstract »    Full Text »    PDF »
Pharmacogenomics: candidate gene identification, functional validation and mechanisms.
L. Wang and R. M. Weinshilboum (2008)
Hum. Mol. Genet. 17, R174-R179
   Abstract »    Full Text »    PDF »
Metabolic and cardiovascular traits: an abundance of recently identified common genetic variants.
K. L. Mohlke, M. Boehnke, and G. R. Abecasis (2008)
Hum. Mol. Genet. 17, R102-R108
   Abstract »    Full Text »    PDF »
Practical aspects of imputation-driven meta-analysis of genome-wide association studies.
P. I.W. de Bakker, M. A.R. Ferreira, X. Jia, B. M. Neale, S. Raychaudhuri, and B. F. Voight (2008)
Hum. Mol. Genet. 17, R122-R128
   Abstract »    Full Text »    PDF »
Genome-wide association studies: potential next steps on a genetic journey.
M. I. McCarthy and J. N. Hirschhorn (2008)
Hum. Mol. Genet. 17, R156-R165
   Abstract »    Full Text »    PDF »
Genome-Wide Approaches to Finding Novel Genes for Lipid Traits: The Start of a Long Road.
A. C. Edmondson and D. J. Rader (2008)
Circ Cardiovasc Genet 1, 3-6
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Review: Genetics of diabetic nephropathy.
S. Maeda (2008)
Therapeutic Advances in Cardiovascular Disease 2, 363-371
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Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication.
D. I. Chasman, G. Pare, R. Y.L. Zee, A. N. Parker, N. R. Cook, J. E. Buring, D. J. Kwiatkowski, L. M. Rose, J. D. Smith, P. T. Williams, et al. (2008)
Circ Cardiovasc Genet 1, 21-30
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Cardiovascular Genomics, Personalized Medicine, and the National Heart, Lung, and Blood Institute: Part I: The Beginning of an Era.
C. J. O'Donnell and E. G. Nabel (2008)
Circ Cardiovasc Genet 1, 51-57
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HapMap and Mapping Genes for Cardiovascular Disease.
K. Musunuru and S. Kathiresan (2008)
Circ Cardiovasc Genet 1, 66-71
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