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)
Mark I. McCarthy,1,2
Andrew T. Hattersley3,4
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.
Membership of the WTCCC is listed at the end of this paper.
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: mark.mccarthy{at}drl.ox.ac.uk
