Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Paul R. BurtonDepartment of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.,David G. ClaytonDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,Lon R. CardonWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,Nick CraddockDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Panos DeloukasThe Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.,Audrey DuncansonThe Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.,Dominic KwiatkowskiWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,Mark I. McCarthyWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,Willem H. OuwehandDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Nilesh J. SamaniDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.,John A. ToddDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,Peter DonnellyDepartment of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.,Jeffrey C. BarrettWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,Paul R. BurtonDepartment of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.,Dan DavisonDepartment of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.,Peter DonnellyDepartment of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.,Doug EastonCancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.,David EvansWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,Hin-Tak LeungDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,Jonathan L. MarchiniDepartment of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.,Andrew P. MorrisWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,Chris C. A. SpencerDepartment of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.,Martin D. TobinDepartment of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.,Lon R. CardonWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.,David G. ClaytonDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,Antony AttwoodThe Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.,James P. BoormanDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Barbara CantDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Ursula EversonNational Health Service Blood and Transplant, Sheffield Centre, Longley Lane, Sheffield S5 7JN, UK.,Judith M. HusseyNational Health Service Blood and Transplant, Brentwood Centre, Crescent Drive, Brentwood CM15 8DP, UK.,Jennifer D. JolleyDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Alexandra S. KnightDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Kerstin KochDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Elizabeth MeechThe Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun CF72 9WB, UK.,Sarah NutlandDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,C V ProwseThe Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh EH17 7QT, UK.,Helen E. StevensDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,Niall TaylorDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Graham R. WaltersNational Health Service Blood and Transplant, Southampton Centre, Coxford Road, Southampton SO16 5AF, UK.,Neil M. WalkerDepartment of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.,Nicholas A. WatkinsDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Thilo WinzerDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,Willem H. OuwehandDepartment of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.,1958 Birth Cohort ControlsAvon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.,Richard W. JonesAvon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.,Wendy L. McArdleAvon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.,Susan M. RingDivision of Community Health Services, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.,David P. StrachanAvon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.,Marcus PembreyUniversity of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.,Bipolar DisorderThe Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.,Gerome BreenDepartment of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.,David St ClairDepartment of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.,Sian CaesarAvon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.,Katherine Gordon‐SmithDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Lisa JonesDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Christine FraserDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Elaine GreenDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Detelina GrozevaDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Marian L. HamshereDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Peter HolmansDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Ian JonesDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,George KirovDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Valentina MoskvinaDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Ivan NikolovDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Michael O‘DonovanDepartment of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.,Michael J. OwenSGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.,Nick CraddockSGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.,David CollierSGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.,Amanda ElkinSGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.,Anne FarmerDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.,Richard WilliamsonSchool of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.,Peter McGuffinAllan H. YoungLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,I. Nicol FerrierLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,Coronary Artery DiseaseLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,Stephen G. BallLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,Anthony J. BalmforthLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,Jennifer H. BarrettLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,D. Timothy BishopLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,Mark M. IlesLIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.,Azhar MaqboolDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.,Nadira YuldashevaDepartment of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.,Alistair S. HallDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.,Peter S. BraundDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.,Richard J. DixonDepartment of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.,Massimo ManginoDepartment of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.,Suzanne StevensDepartment of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.,Martin D. TobinIBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.,J. ThompsonIBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.,Nilesh J. SamaniAddenbrooke's HospitalCrohn’s DiseaseGastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.,Francesca BredinGastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.,Mark TremellingGastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.,Miles ParkesHazel E. DrummondDepartment of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.,Charles W. LeesInstitute for Digestive Diseases, University College London Hospitals Trust, London, NW1 2BU, UK.,Elaine R. NimmoDepartment of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.,Jack SatsangiDepartment of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.,
2007en
ABI
Аннотация
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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