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Originally published in Science Express on 26 April 2007
Science 1 June 2007:
Vol. 316. no. 5829, pp. 1341 - 1345
DOI: 10.1126/science.1142382
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Reports

A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants

Laura J. Scott,1 Karen L. Mohlke,2 Lori L. Bonnycastle,3 Cristen J. Willer,1 Yun Li,1 William L. Duren,1 Michael R. Erdos,3 Heather M. Stringham,1 Peter S. Chines,3 Anne U. Jackson,1 Ludmila Prokunina-Olsson,3 Chia-Jen Ding,1 Amy J. Swift,3 Narisu Narisu,3 Tianle Hu,1 Randall Pruim,4 Rui Xiao,1 Xiao-Yi Li,1 Karen N. Conneely,1 Nancy L. Riebow,3 Andrew G. Sprau,3 Maurine Tong,3 Peggy P. White,1 Kurt N. Hetrick,5 Michael W. Barnhart,5 Craig W. Bark,5 Janet L. Goldstein,5 Lee Watkins,5 Fang Xiang,1 Jouko Saramies,6 Thomas A. Buchanan,7 Richard M. Watanabe,8,9 Timo T. Valle,10 Leena Kinnunen,10,11 Gonçalo R. Abecasis,1 Elizabeth W. Pugh,5 Kimberly F. Doheny,5 Richard N. Bergman,9 Jaakko Tuomilehto,10,11,12 Francis S. Collins,3* Michael Boehnke1*

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.

1 Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
2 Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
3 Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
4 Department of Mathematics and Statistics, Calvin College, Grand Rapids, MI 49546, USA.
5 Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.
6 Savitaipale Health Center, 54800 Savitaipale, Finland.
7 Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
8 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
9 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
10 Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.
11 Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.
12 South Ostrobothnia Central Hospital, 60220 Seinäjoki, Finland.

* To whom correspondence should be addressed. E-mail: boehnke{at}umich.edu (M.B.); francisc{at}mail.nih.gov (F.S.C.)

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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
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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 »
Lifetime body mass index and later atherosclerosis risk in young adults: examining causal links using Mendelian randomization in the Cardiovascular Risk in Young Finns study.
M. Kivimaki, G. D. Smith, N. J. Timpson, D. A. Lawlor, G. D. Batty, M. Kahonen, M. Juonala, T. Ronnemaa, J. S.A. Viikari, T. Lehtimaki, et al. (2008)
Eur. Heart J. 29, 2552-2560
   Abstract »    Full Text »    PDF »
Review: Genetics of diabetic nephropathy.
S. Maeda (2008)
Therapeutic Advances in Cardiovascular Disease 2, 363-371
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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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Impact of TCF7L2 rs7903146 on Insulin Secretion and Action in Young and Elderly Danish Twins.
L. Wegner, M. S. Hussain, K. Pilgaard, T. Hansen, O. Pedersen, A. Vaag, and P. Poulsen (2008)
J. Clin. Endocrinol. Metab. 93, 4013-4019
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Zinc Transporter-8 Gene (SLC30A8) Is Associated with Type 2 Diabetes in Chinese.
J. Xiang, X.-Y. Li, M. Xu, J. Hong, Y. Huang, J.-R. Tan, X. Lu, M. Dai, B. Yu, and G. Ning (2008)
J. Clin. Endocrinol. Metab. 93, 4107-4112
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A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes.
J. M. Wenzlau, Y. Liu, L. Yu, O. Moua, K. T. Fowler, S. Rangasamy, J. Walters, G. S. Eisenbarth, H. W. Davidson, and J. C. Hutton (2008)
Diabetes 57, 2693-2697
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Common Variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE Genes Are Associated With Type 2 Diabetes and Impaired Fasting Glucose in a Chinese Han Population.
Y. Wu, H. Li, R. J.F. Loos, Z. Yu, X. Ye, L. Chen, A. Pan, F. B. Hu, and X. Lin (2008)
Diabetes 57, 2834-2842
   Abstract »    Full Text »    PDF »
Epithelial Sodium Channel: Mendelian Versus Essential Hypertension.
B. C. Rossier and L. Schild (2008)
Hypertension 52, 595-600
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Physical Activity and the Association of Common FTO Gene Variants With Body Mass Index and Obesity.
E. Rampersaud, B. D. Mitchell, T. I. Pollin, M. Fu, H. Shen, J. R. O'Connell, J. L. Ducharme, S. Hines, P. Sack, R. Naglieri, et al. (2008)
Arch Intern Med 168, 1791-1797
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Genomewide Association Analysis Followed by a Replication Study Implicates a Novel Candidate Gene for Neuroticism.
E. J. C. G. van den Oord, P.-H. Kuo, A. M. Hartmann, B. T. Webb, H.-J. Moller, J. M. Hettema, I. Giegling, J. Bukszar, and D. Rujescu (2008)
Arch Gen Psychiatry 65, 1062-1071
   Abstract »    Full Text »    PDF »
The search for genes contributing to endometriosis risk.
G. W. Montgomery, D. R. Nyholt, Z. Z. Zhao, S. A. Treloar, J. N. Painter, S. A. Missmer, S. H. Kennedy, and K. T. Zondervan (2008)
Hum. Reprod. Update 14, 447-457
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Exclusion of Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) as a Cause of Diabetic Nephropathy in Type 1 Diabetes: Results of Large Case-Control and Follow-Up Studies.
K. Wanic, G. Placha, J. Dunn, A. Smiles, J. H. Warram, and A. S. Krolewski (2008)
Diabetes 57, 2547-2551
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Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program.
A. F. Moore, K. A. Jablonski, J. B. McAteer, R. Saxena, T. I. Pollin, P. W. Franks, R. L. Hanson, A. R. Shuldiner, W. C. Knowler, D. Altshuler, et al. (2008)
Diabetes 57, 2503-2510
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Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes.
N. Grarup, G. Andersen, N. T. Krarup, A. Albrechtsen, O. Schmitz, T. Jorgensen, K. Borch-Johnsen, T. Hansen, and O. Pedersen (2008)
Diabetes 57, 2534-2540
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A Weighted-Holm Procedure Accounting for Allele Frequencies in Genomewide Association Studies.
C. Dalmasso, E. Genin, and D.-A. Tregouet (2008)
Genetics 180, 697-702
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Evidence that the gene encoding insulin degrading enzyme influences human lifespan.
M.-G. Hong, C. Reynolds, M. Gatz, B. Johansson, J. C. Palmer, H. F. Gu, K. Blennow, P. G. Kehoe, U. de Faire, N. L. Pedersen, et al. (2008)
Hum. Mol. Genet. 17, 2370-2378
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