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Originally published in Science Express on 26 April 2007
Science 1 June 2007:
Vol. 316. no. 5829, pp. 1336 - 1341
DOI: 10.1126/science.1142364
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Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes

Eleftheria Zeggini,1,2* Michael N. Weedon,3,4* Cecilia M. Lindgren,1,2* Timothy M. Frayling,3,4* Katherine S. Elliott,2 Hana Lango,3,4 Nicholas J. Timpson,2,5 John R. B. Perry,3,4 Nigel W. Rayner,1,2 Rachel M. Freathy,3,4 Jeffrey C. Barrett,2 Beverley Shields,4 Andrew P. Morris,2 Sian Ellard,4,6 Christopher J. Groves,1 Lorna W. Harries,4 Jonathan L. Marchini,7 Katharine R. Owen,1 Beatrice Knight,4 Lon R. Cardon,2 Mark Walker,8 Graham A. Hitman,9 Andrew D. Morris,10 Alex S. F. Doney,10 The Wellcome Trust Case Control Consortium (WTCCC){dagger} Mark I. McCarthy,1,2{ddagger}§ Andrew T. Hattersley3,4{ddagger}

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.

1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
2 The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX37BN, UK.
3 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.
4 Diabetes Genetics Group, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.
5 Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Rd, Bristol, BS2 8PR, UK.
6 The Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Old Pathology Building, Barrack Road, Exeter, EX2 5DW, UK.
7 Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK.
8 Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
9 Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London, E1 1BB, UK.
10 Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.

* These authors contributed equally to this work.

{dagger} Membership of the WTCCC is listed at the end of this paper.

{ddagger} These authors contributed equally to this work.

§ To whom correspondence should be addressed. E-mail: mark.mccarthy{at}drl.ox.ac.uk

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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 »
Genetic Mapping in Human Disease.
D. Altshuler, M. J. Daly, and E. S. Lander (2008)
Science 322, 881-888
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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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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
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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
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Fat Mass-and Obesity-Associated (FTO) Gene Variant Is Associated With Obesity: Longitudinal Analyses in Two Cohort Studies and Functional Test.
L. Qi, K. Kang, C. Zhang, R. M. van Dam, P. Kraft, D. Hunter, C.-H. Lee, and F. B. Hu (2008)
Diabetes 57, 3145-3151
   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
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