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Published Online April 26, 2007
Science DOI: 10.1126/science.1142364

Reports

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

Replication of Genome-Wide Association Signals in U.K. Samples Reveals Risk Loci for Type 2 Diabetes

Eleftheria Zeggini 1, Michael N. Weedon 2, Cecilia M. Lindgren 1, Timothy M. Frayling 2, Katherine S. Elliott 3, Hana Lango 2, Nicholas J. Timpson 4, John R. B. Perry 2, Nigel W. Rayner 1, Rachel M. Freathy 2, Jeffrey C. Barrett 3, Beverley Shields 5, Andrew P. Morris 3, Sian Ellard 6, Christopher J. Groves 7, Lorna W. Harries 5, Jonathan L. Marchini 8, Katharine R. Owen 7, Beatrice Knight 5, Lon R. Cardon 3, Mark Walker 9, Graham A. Hitman 10, Andrew D. Morris 11, Alex S. F. Doney 11, The Wellcome Trust Case Control Consortium , Mark I. McCarthy 1*, Andrew T. Hattersley 2

1 Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
2 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.; Diabetes Genetics group, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.
3 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
4 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Rd, Bristol, BS2 8PR, UK.
5 Diabetes Genetics group, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.
6 Diabetes Genetics group, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.; The Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Old Pathology Building, Barrack Road, Exeter, EX2 5DW, UK.
7 Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
8 Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK
9 Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
10 Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London, E1 1BB, UK.
11 Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.

* To whom correspondence should be addressed.
Mark I. McCarthy , E-mail: mark.mccarthy{at}drl.ox.ac.uk

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.


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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
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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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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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Aliskiren.
M. J. Brown (2008)
Circulation 118, 773-784
   Abstract »    Full Text »    PDF »
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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Genetic Analysis of Kruppel-Like Zinc Finger 11 Variants in 5864 Danish Individuals: Potential Effect on Insulin Resistance and Modified Signal Transducer and Activator of Transcription-3 Binding by Promoter Variant -1659G>C.
R. Gutierrez-Aguilar, P. Froguel, Y. H. Hamid, Y. Benmezroua, T. Jorgensen, K. Borch-Johnsen, T. Hansen, O. Pedersen, and B. Neve (2008)
J. Clin. Endocrinol. Metab. 93, 3128-3135
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Association Analysis in African Americans of European-Derived Type 2 Diabetes Single Nucleotide Polymorphisms From Whole-Genome Association Studies.
J. P. Lewis, N. D. Palmer, P. J. Hicks, M. M. Sale, C. D. Langefeld, B. I. Freedman, J. Divers, and D. W. Bowden (2008)
Diabetes 57, 2220-2225
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Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians.
M. C.Y. Ng, K. S. Park, B. Oh, C. H.T. Tam, Y. M. Cho, H. D. Shin, V. K.L. Lam, R. C.W. Ma, W. Y. So, Y. S. Cho, et al. (2008)
Diabetes 57, 2226-2233
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Common Variation in the Fat Mass and Obesity-Associated (FTO) Gene Confers Risk of Obesity and Modulates BMI in the Chinese Population.
Y.-C. Chang, P.-H. Liu, W.-J. Lee, T.-J. Chang, Y.-D. Jiang, H.-Y. Li, S.-S. Kuo, K.-C. Lee, and L.-M. Chuang (2008)
Diabetes 57, 2245-2252
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Exchangeable Models of Complex Inherited Diseases.
M. Slatkin (2008)
Genetics 179, 2253-2261
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Gaining Insights in Coronary Disease Genomics.
S. S. Murray and E. J. Topol (2008)
J. Am. Coll. Cardiol. 52, 385-386
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