Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Abstract

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

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Affiliated Institutions

• University of Cambridge GB
• King's College London GB
• St George's, University of London GB
• University College Hospital GB
• University College London GB
• Wellcome Trust GB
• University of Oxford GB
• Glenfield Hospital GB
• National Health Service GB
• Scottish National Blood Transfusion Service GB
• Welsh Government GB
• University of Aberdeen GB
• Addenbrooke's Hospital GB
• Western General Hospital GB
• University of Bristol GB
• University of Edinburgh GB
• Royal Victoria Infirmary GB
• University of Leicester GB
• Cancer Research UK GB
• Centre for Human Genetics GB
• University of Birmingham GB
• Guy's Hospital GB
• Wellcome Sanger Institute GB
• University of Leeds GB
• Cardiff University GB
• Université Bourgogne Franche-Comté FR
• Juvenile Diabetes Research Foundation GB

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