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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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Am. J. Epidemiol. 169, 54-66
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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
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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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Genetic Mapping in Human Disease.
D. Altshuler, M. J. Daly, and E. S. Lander (2008)
Science 322, 881-888
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Introduction to the Special Issue on Society and Genetics.
Guang Guo (2008)
Sociological Methods Research 37, 159-163
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Severe Intrauterine Growth Retardation and Atypical Diabetes Associated with a Translocation Breakpoint Disrupting Regulation of the Insulin-Like Growth Factor 2 Gene.
R. Murphy, J. Baptista, J. Holly, A. M. Umpleby, S. Ellard, L. W. Harries, J. Crolla, T. Cundy, and A. T. Hattersley (2008)
J. Clin. Endocrinol. Metab. 93, 4373-4380
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Primer: Immunity and Autoimmunity.
M. Pietropaolo, J. M. Surhigh, P. W. Nelson, and G. S. Eisenbarth (2008)
Diabetes 57, 2872-2882
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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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An Appreciation of Robert Turner.
S. O'Rahilly, G. C. Weir, and D. R. Matthews (2008)
Diabetes 57, 2918-2921
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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
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