Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Paul R. Burton(University of Leicester), David G. Clayton(Juvenile Diabetes Research Foundation), Lon R. Cardon(Centre for Human Genetics), Nick Craddock(Cardiff University), Panos Deloukas(Wellcome Sanger Institute), Audrey Duncanson(Wellcome Trust), Dominic Kwiatkowski(Centre for Human Genetics), Mark I. McCarthy(Centre for Human Genetics), Willem H. Ouwehand(University of Cambridge), Nilesh J. Samani(University of Leicester), John A. Todd(Juvenile Diabetes Research Foundation), Peter Donnelly(University of Oxford), Jeffrey C. Barrett(Centre for Human Genetics), Paul R. Burton(University of Leicester), Dan Davison(University of Oxford), Peter Donnelly(University of Oxford), Doug Easton(Cancer Research UK), David Evans(Centre for Human Genetics), Hin-Tak Leung(Juvenile Diabetes Research Foundation), Jonathan L. Marchini(University of Oxford), Andrew P. Morris(Centre for Human Genetics), Chris C. A. Spencer(University of Oxford), Martin D. Tobin(University of Leicester), Lon R. Cardon(Centre for Human Genetics), David G. Clayton(Juvenile Diabetes Research Foundation), Antony Attwood(Wellcome Sanger Institute), James P. Boorman(University of Cambridge), Barbara Cant(University of Cambridge), Ursula Everson(National Health Service), Judith M. Hussey(National Health Service), Jennifer D. Jolley(University of Cambridge), Alexandra S. Knight(University of Cambridge), Kerstin Koch(University of Cambridge), Elizabeth Meech(Welsh Government), Sarah Nutland(Juvenile Diabetes Research Foundation), C V Prowse(Scottish National Blood Transfusion Service), Helen E. Stevens(Juvenile Diabetes Research Foundation), Niall Taylor(University of Cambridge), Graham R. Walters(National Health Service), Neil M. Walker(Juvenile Diabetes Research Foundation), Nicholas A. Watkins(University of Cambridge), Thilo Winzer(University of Cambridge), John A. Todd(Juvenile Diabetes Research Foundation), Willem H. Ouwehand(University of Cambridge), 1958 Birth Cohort Controls(University of Bristol), Richard W. Jones(University of Bristol), Wendy L. McArdle(University of Bristol), Susan M. Ring(St George's, University of London), David P. Strachan(University of Bristol), Marcus Pembrey(University of Aberdeen), Bipolar Disorder(Wellcome Sanger Institute), Gerome Breen(University of Birmingham), David St Clair(University of Birmingham), Sian Caesar(University of Bristol), Katherine Gordon‐Smith(Cardiff University), Lisa Jones(Cardiff University), Christine Fraser(Cardiff University), Elaine Green(Cardiff University), Detelina Grozeva(Cardiff University), Marian L. Hamshere(Cardiff University), Peter Holmans(Cardiff University), Ian Jones(Cardiff University), George Kirov(Cardiff University), Valentina Moskvina(Cardiff University), Ivan Nikolov(Cardiff University), Michael O‘Donovan(Cardiff University), Michael J. Owen(King's College London), Nick Craddock(King's College London), David Collier(King's College London), Amanda Elkin(King's College London), Anne Farmer(University of Leicester), Richard Williamson(Royal Victoria Infirmary), Peter McGuffin, Allan H. Young(University of Leeds), I. Nicol Ferrier(University of Leeds), Coronary Artery Disease(University of Leeds), Stephen G. Ball(University of Leeds), Anthony J. Balmforth(University of Leeds), Jennifer H. Barrett(University of Leeds), D. Timothy Bishop(University of Leeds), Mark M. Iles(University of Leeds), Azhar Maqbool(University of Leicester), Nadira Yuldasheva(University of Leicester), Alistair S. Hall(University of Leicester), Peter S. Braund(University of Leicester), Paul R. Burton(University of Leicester), Richard J. Dixon(University of Leicester), Massimo Mangino(University of Leicester), Suzanne Stevens(University of Leicester), Martin D. Tobin(University of Cambridge), J. Thompson(University of Cambridge), Nilesh J. Samani(University of Cambridge), Crohn’s Disease(Western General Hospital), Francesca Bredin(Western General Hospital), Mark Tremelling(Western General Hospital), Miles Parkes, Hazel E. Drummond(Guy's Hospital), Charles W. Lees(University College Hospital), Elaine R. Nimmo(Guy's Hospital), Jack Satsangi(Guy's Hospital), Sheila Fisher(Guy's Hospital), Alastair Forbes(Guy's and St Thomas' NHS Foundation Trust), Cathryn M. Lewis(Guy's Hospital), Clive M. Onnie(Royal Victoria Infirmary), Natalie J. Prescott(Royal Victoria Infirmary), Jeremy Sanderson, Christopher G. Mathew(Royal Victoria Infirmary), Jamie Barbour(University of Oxford), Mohamed Khalid Mohiuddin(University of Oxford), Catherine E Todhunter, John Mansfield(Royal Victoria Infirmary), Tariq Ahmad(University of Cambridge), Fraser Cummings(Juvenile Diabetes Research Foundation), Derek P. Jewell, Hypertension(University of Glasgow), John Webster(University of Manchester), Morris J. Brown(University of Leicester), David G. Clayton(William Harvey Research Institute), G. Mark Lathrop(William Harvey Research Institute), John Connell(William Harvey Research Institute), Anna F. Dominiczak(William Harvey Research Institute), Nilesh J. Samani(William Harvey Research Institute), C Marcano(William Harvey Research Institute), Beverley Burke(William Harvey Research Institute), Richard Dobson(William Harvey Research Institute), Johannie Gungadoo(William Harvey Research Institute), Kate Lee(William Harvey Research Institute), Patricia B. Munroe(William Harvey Research Institute), Stephen Newhouse(Centre for Human Genetics), Abiodun Onipinla(University of Manchester), Chris Wallace, Mingzhan Xue(University of Manchester), Mark J. Caulfield(University of Manchester), Martin Farrall(University of Manchester), Rheumatoid Arthritis(University of Manchester), Anne Barton(University of Manchester), The Biologics in RA Genetics and Genomics(University of Manchester), Ian N Bruce(University of Manchester), Hannah Donovan(University of Manchester), Steve Eyre(University of Manchester), Paul Gilbert(University of Manchester), Samantha Hider(University of Manchester), Anne Hinks(Juvenile Diabetes Research Foundation), Sally John(University of Cambridge), Catherine Potter(Juvenile Diabetes Research Foundation), Alan J. Silman(Juvenile Diabetes Research Foundation), Deborah Symmons(Juvenile Diabetes Research Foundation), Wendy Thomson(University of Cambridge), Jane Worthington(Juvenile Diabetes Research Foundation), Type 1 Diabetes(Peninsula College of Medicine and Dentistry), David G. Clayton(Peninsula College of Medicine and Dentistry), David B. Dunger(Peninsula College of Medicine and Dentistry), Sarah Nutland(Peninsula College of Medicine and Dentistry), Helen E. Stevens(Peninsula College of Medicine and Dentistry), Neil M. Walker(Peninsula College of Medicine and Dentistry), Barry Widmer(Peninsula College of Medicine and Dentistry), John A. Todd(National Health Service), Type 2 Diabetes(Juvenile Diabetes Research Foundation), Timothy M. Frayling(Churchill Hospital), Rachel M. Freathy(Churchill Hospital), Hana Lango(Churchill Hospital), John R. B. Perry(Churchill Hospital), Beverley M. Shields(University of Bristol), Michael N. Weedon(Churchill Hospital), Andrew T. Hattersley(Churchill Hospital), G. A. Hitman(MRC Unit the Gambia), Mark S. Walker, Kate Elliott(Centre for Human Genetics), Christopher J. Groves(Centre for Human Genetics), Cecilia M. Lindgren(Centre for Human Genetics), Nigel W. Rayner(The University of Queensland), Nicholas J. Timpson(University of Oxford), Eleftheria Zeggini(The University of Queensland), Mark I. McCarthy(University of Oxford), Tuberculosis(The University of Queensland), Melanie J. Newport(University of Birmingham), Giorgio Sirugo(University of Birmingham), Emily Lyons(University of Birmingham), Fredrik Vannberg(University of Birmingham), Adrian V. S. Hill(Institute of Cancer Research), Ankylosing Spondylitis, Linda A. Bradbury(Institute of Cancer Research), Claire Farrar(Institute of Cancer Research), Jennifer J. Pointon(University of Cambridge), B P Wordsworth(University of Cambridge), Matthew A. Brown(University of Cambridge), Autoimmune Thyroid Disease(University of Cambridge), Jayne A. Franklyn(MRC Unit the Gambia), J. M. Heward(MRC Unit the Gambia), Matthew J. Simmonds(MRC Unit the Gambia), Stephen C. L. Gough, Breast Cancer(Centre for Human Genetics), Sheila Seal(Wellcome Sanger Institute), Michael R. Stratton(Wellcome Sanger Institute), Nazneen Rahman(Wellcome Sanger Institute), Multiple Sclerosis(Wellcome Sanger Institute), Maria Ban(Wellcome Sanger Institute), An Goris(Wellcome Sanger Institute), Stephen Sawcer(Wellcome Sanger Institute), Alastair Compston(Wellcome Sanger Institute), Gambian Controls(Wellcome Sanger Institute), David J. Conway(Wellcome Sanger Institute), Muminatou Jallow(Wellcome Sanger Institute), Melanie J. Newport(Wellcome Sanger Institute), Giorgio Sirugo(Wellcome Sanger Institute), Kirk A. Rockett(Wellcome Sanger Institute), Dominic Kwiatkowski(Wellcome Sanger Institute), DNA, Genotyping, Data QC and Informatics(Wellcome Sanger Institute), Suzannah J. Bumpstead(Wellcome Sanger Institute), Amy Chaney(Juvenile Diabetes Research Foundation), Kate Downes(Juvenile Diabetes Research Foundation), Mohammed J. R. Ghori(Juvenile Diabetes Research Foundation), Rhian Gwilliam(Juvenile Diabetes Research Foundation), Sarah Hunt(Juvenile Diabetes Research Foundation), Michael Inouye(Cancer Research UK), Andrew Keniry(Juvenile Diabetes Research Foundation), Emma King(University of Leicester), Ralph McGinnis(University of Leicester), Simon Potter(Centre for Human Genetics), Rathi Ravindrarajah(Centre for Human Genetics), Pamela Whittaker(Centre for Human Genetics), Claire Widden(Centre for Human Genetics), David Withers(University of Oxford), Panos Deloukas(University of Oxford), Hin-Tak Leung(University of Oxford), Sarah Nutland(University of Oxford), Helen E. Stevens(University of Oxford), Neil M. Walker(University of Oxford), John A. Todd(University of Oxford), Statistics(University of Oxford), Doug Easton(University of Oxford), David G. Clayton(University of Oxford), Paul R. Burton(University of Oxford), Martin D. Tobin(University of Oxford), Jeffrey C. Barrett(Wellcome Sanger Institute), David Evans(University of Oxford), Andrew P. Morris(Centre for Human Genetics), Lon R. Cardon(William Harvey Research Institute), Niall J. Cardin(Juvenile Diabetes Research Foundation), Dan Davison(University of Cambridge), Teresa Ferreira(Cardiff University), Joanne Pereira-Gale(Wellcome Sanger Institute), Ingileif B. Hallgrímsdóttir(University of Oxford), Bryan Howie(Centre for Human Genetics), Jonathan L. Marchini(University of Birmingham), Chris C. A. Spencer(University of Leeds), Zhan Su(Peninsula College of Medicine and Dentistry), Yik Ying Teo(Centre for Human Genetics), Damjan Vukcevic(Wellcome Sanger Institute), Peter Donnelly(Guy's Hospital), Primary Investigators(Churchill Hospital), David Bentley(National Health Service), Matthew A. Brown(University of Cambridge), Lon R. Cardon(University College London), Mark J. Caulfield(Institute of Cancer Research), David G. Clayton(University of Leicester), Alistair Compston(Wellcome Sanger Institute), Nick Craddock(Juvenile Diabetes Research Foundation), Panos Deloukas(University of Manchester), Peter Donnelly, Martin Farrall, Stephen C. L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V. S. Hill, Dominic Kwiatkowski, Christopher G. Mathew, Mark I. McCarthy, Willem H. Ouwehand, Miles Parkes, Marcus Pembrey, Nazneen Rahman, Nilesh J. Samani, Michael R. Stratton, John A. Todd, Jane Worthington
Cited by 9,628Open Access
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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