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

2007; Nature Portfolio; Volume: 447; Issue: 7145 Linguagem: Inglês

10.1038/nature05911

1476-4687

Paul R. Burton, David Clayton, Lon R. Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Nilesh J. Samani, John A. Todd, Peter Donnelly, Jeffrey C. Barrett, Paul R. Burton, Doug Easton, Peter Donnelly, H.T. Leung, Jonathan L. Marchini, Andrew P. Morris, Jonathan L. Marchini, Martin D. Tobin, Antony Attwood, Martin D. Tobin, Lon R. Cardon, David Clayton, Antony Attwood, James P. Boorman, Barbara Cant, Ursula Everson, Judith M. Hussey, Jennifer D. Jolley, Alexandra S. Knight, Kerstin Koch, Elizabeth Meech, Nicholas J. Timpson, C V Prowse, Eleftheria Zeggini, Niall Taylor, Graham R. Walters, Melanie J. Newport, Nicholas A. Watkins, Thilo Winzer, John A. Todd, Willem H. Ouwehand, Richard W. Jones, Wendy L. McArdle, Susan M. Ring, David P. Strachan, Marcus Pembrey, Gerome Breen, David St Clair, Sian Caesar, Katherine Gordon‐Smith, Lisa Jones, Christine Fraser, Elaine Green, Detelina Grozeva, Marian L. Hamshere, Peter Holmans, Ian Jones, George Kirov, Valentina Moskvina, Ivan Nikolov, Michael O’Donovan, Michael J. Owen, Nick Craddock, David Collier, Amanda Elkin, Anne Farmer, Richard Williamson, Peter McGuffin, Allan H. Young, I. Nicol Ferrier, Stephen G. Ball, Anthony J. Balmforth, Jennifer H. Barrett, D. Timothy Bishop, Mark M. Iles, Azhar Maqbool, Nadira Yuldasheva, Alistair S. Hall, Peter S. Braund, Paul R. Burton, Richard J. Dixon, Massimo Mangino, Suzanne Stevens, Martin D. Tobin, J. Thompson, Nilesh J. Samani, Francesca Bredin, Mark Tremelling, Miles Parkes, Hazel E. Drummond, Charlie W. Lees, Elaine R. Nimmo, Jack Satsangi, Sheila Fisher, Alastair Forbes, Cathryn M. Lewis, Clive M. Onnie, Natalie J. Prescott, Jeremy Sanderson, G. Mark Lathrop, Jamie Barbour, Mohamed Khalid Mohiuddin, Catherine E Todhunter, John Mansfield, Tariq Ahmad, Fraser Cummings, Derek P. Jewell, John Webster, Morris J. Brown, David G. Clayton, G. Mark Lathrop, John Connell, Anna F. Dominiczak, Nilesh J. Samani, C Marcano, Beverley Burke, Richard Dobson, Johannie Gungadoo, Kate Lee, Patricia B. Munroe, Stephen Newhouse, Abiodun Onipinla, Chris Wallace, Mingzhan Xue, Mark J. Caulfield, Martin Farrall, Anne Barton, The Biologics in RA Genetics and Genomics, Ian N Bruce, Hannah Donovan, Stephen Eyre, Paul Gilbert, Samantha Hider, Anne Hinks, Sally John, Catherine Potter, Alan J. Silman, Deborah Symmons, Wendy Thomson, Christopher J. Groves, David G. Clayton, David B. Dunger, Nicholas J. Timpson, Eleftheria Zeggini, Melanie J. Newport, Barry Widmer, John A. Todd, Timothy M. Frayling, Rachel M. Freathy, Hana Lango Allen, John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Matthew A. Brown, G. A. Hitman, Mark S. Walker, Kate Elliott, Christopher J. Groves, Cecilia M. Lindgren, Nigel W. Rayner, Nicholas J. Timpson, Eleftheria Zeggini, Mark I. McCarthy, Melanie J. Newport, A. Compston, Emily J. Lyons, Fredrik Vannberg, Adrian V. S. Hill, Linda A. Bradbury, Claire Farrar, Jennifer J. Pointon, B P Wordsworth, Matthew A. Brown, Jayne A. Franklyn, J. M. Heward, Matthew J. Simmonds, Emma King, Sheila Seal, Breast Cancer Susceptibility Collaboration, Michael R. Stratton, Nazneen Rahman, Maria Ban, An Goris, Stephen Sawcer, Alastair Compston, David J. Conway, Muminatou Jallow, Melanie J. Newport, A. Compston, Adrian V. S. Hill, Dominic Kwiatkowski, Suzannah J. Bumpstead, Amy Chaney, Kate Downes, Mohammed J. R. Ghori, Rhian Gwilliam, Sarah Hunt, Michael Inouye, Andrew Keniry, Emma King, Ralph McGinnis, Simon Potter, Rathi Ravindrarajah, Pamela Whittaker, Claire Widden, David Withers, Panos Deloukas, Andrew P. Morris, Nicholas J. Timpson, Eleftheria Zeggini, Melanie J. Newport, John A. Todd, H.T. Leung, David Clayton, Paul R. Burton, Martin D. Tobin, Jeffrey C. Barrett, Jonathan L. Marchini, Martin D. Tobin, Lon R. Cardon, Niall J. Cardin, Doug Easton, Teresa Ferreira, Joanne Pereira-Gale, Ingileif B. Hallgrímsdóttir, Bryan Howie, Jonathan L. Marchini, Antony Attwood, Zhan Su, Yik Ying Teo, Damjan Vukcevic, Peter Donnelly, David Bentley, Matthew A. Brown, Lon R. Cardon, Mark J. Caulfield, David Clayton, Alistair Compston, Nick Craddock, Panos Deloukas, Peter Donnelly, Martin Farrall, Emma King, Alistair S. Hall, Matthew A. Brown, Adrian V. S. Hill, Dominic Kwiatkowski, G. Mark Lathrop, Mark I. McCarthy, Willem H. Ouwehand, Miles Parkes, Marcus Pembrey, Nazneen Rahman, Nilesh J. Samani, Michael R. Stratton, John A. Todd, Christopher J. Groves,

Genomic variations and chromosomal abnormalities

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 ∼2,000 individuals for each of 7 major diseases and a shared set of ∼3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 × 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 × 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. With the advent of many more markers in the human genome, it has become possible to search for genes associated with human disease without having to narrow down candidate regions of the genome first. In a ground-breaking publication, the Wellcome Trust Case Control Consortium reports an exciting genome-wide association study of some 17,000 individuals for seven common familial diseases. The analysis confirms previously identified loci and provides strong evidence for many novel disease susceptibility genes. An exciting genome-wide association study in the British population for seven common diseases. This analysis confirms previously identified loci and provides strong evidence for many novel disease susceptibility loci.