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Published Online April 26, 2007
Science DOI: 10.1126/science.1142382

Reports

Submitted on March 12, 2007
Accepted on April 20, 2007

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, Timo T. Valle 9, Leena Kinnunen 10, Goncalo R. Abecasis 1, Elizabeth W. Pugh 5, Kimberly F. Doheny 5, Richard N. Bergman 11, Jaakko Tuomilehto 12, Francis S. Collins 3*, Michael Boehnke 1*

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, 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.; Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
9 Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.
10 Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.; Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.
11 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
12 Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.; Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.; South Ostrobothnia Central Hospital, 60220 Seinajoki, Finland.

* To whom correspondence should be addressed.
Francis S. Collins , E-mail: francisc{at}mail.nih.gov
Michael Boehnke , E-mail: boehnke{at}umich.edu

Identifying the genetic variants that increase risk of type 2 diabetes (T2D) has been a formidable challenge. Adopting a genome wide association strategy, we genotyped 1,161 Finnish T2D cases and 1,174 Finnish normal glucose tolerant (NGT) controls with >315,000 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 results of two other such studies, and genotyped 80 SNPs in an additional 1,215 Finnish T2D cases and 1,258 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, CDKAL1, and CDKN2A/CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings to at least ten the number of T2D loci now confidently identified.


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Size matters: just how big is BIG?: Quantifying realistic sample size requirements for human genome epidemiology.
P. R Burton, A. L Hansell, I. Fortier, T. A Manolio, M. J Khoury, J. Little, and P. Elliott (2009)
Int. J. Epidemiol. 38, 263-273
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Association Analysis of Variation in/Near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B With Type 2 Diabetes and Related Quantitative Traits in Pima Indians.
R. Rong, R. L. Hanson, D. Ortiz, C. Wiedrich, S. Kobes, W. C. Knowler, C. Bogardus, and L. J. Baier (2009)
Diabetes 58, 478-488
   Abstract »    Full Text »    PDF »
Replication Study of Candidate Genes Associated With Type 2 Diabetes Based On Genome-Wide Screening.
Y. Tabara, H. Osawa, R. Kawamoto, H. Onuma, I. Shimizu, T. Miki, K. Kohara, and H. Makino (2009)
Diabetes 58, 493-498
   Abstract »    Full Text »    PDF »
Adiposity-Related Heterogeneity in Patterns of Type 2 Diabetes Susceptibility Observed in Genome-Wide Association Data.
N. J. Timpson, C. M. Lindgren, M. N. Weedon, J. Randall, W. H. Ouwehand, D. P. Strachan, N. W. Rayner, M. Walker, G. A. Hitman, A. S.F. Doney, et al. (2009)
Diabetes 58, 505-510
   Abstract »    Full Text »    PDF »
Genetic Epidemiology in Aging Research.
M. D. Fallin and A. Matteini (2009)
J Gerontol A Biol Sci Med Sci
   Abstract »    Full Text »    PDF »
Cardiovascular Disease Risk Prediction With and Without Knowledge of Genetic Variation at Chromosome 9p21.3.
N. P. Paynter, D. I. Chasman, J. E. Buring, D. Shiffman, N. R. Cook, and P. M. Ridker (2009)
Ann Intern Med 150, 65-72
   Abstract »    Full Text »    PDF »
GWAS GUI: graphical browser for the results of whole-genome association studies with high-dimensional phenotypes.
W. Chen, L. Liang, and G. R. Abecasis (2009)
Bioinformatics 25, 284-285
   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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
A Genome-Wide Association Study of Schizophrenia Using Brain Activation as a Quantitative Phenotype.
S. G. Potkin, J. A. Turner, G. Guffanti, A. Lakatos, J. H. Fallon, D. D. Nguyen, D. Mathalon, J. Ford, J. Lauriello, F. Macciardi, et al. (2009)
Schizophr Bull 35, 96-108
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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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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
   Abstract »    Full Text »    PDF »
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
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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
   Abstract »    Full Text »    PDF »


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