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

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posted on 2023-06-07, 16:05 authored by Paul R. Burton, David G. Clayton, Lon R. Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P. Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Nilesh J. Samani, John A. Todd, Peter Donnelly, Jeffrey C. Barrett, Dan Davison, Doug Easton, David Evans, Hin-Tak Leung, Jonathan L. Marchini, Andrew P. Morris, Chris C.A. Spencer, Martin D. Tobin, Antony P. Attwood, James P. Boorman, Barbara Cant, Ursula Everson, Judith M. Hussey, Jennifer D. Jolley, Alexandra S. Knight, Kerstin Koch, Elizabeth Meech, Sarah Nutland, Christopher V. Prowse, Helen E. Stevens, Niall C. Taylor, Graham R. Walters, Neil M. Walker, Nicholas A. Watkins, Thilo Winzer, 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, Elain K. Green, Detelina Grozeva, Marian L. Hamshere, Peter A. Holmans, Ian R. Jones, George Kirov, Valentina Moskvina, Ivan Nikolov, Michael C. O'Donovan, Michael J. Owen, David A. 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, Richard J. Dixon, Massimo Mangino, Suzanne Stevens, John R. Thompson, Francesca Bredin, Mark Tremelling, Miles Parkes, Hazel Drummond, Charles W. Lees, Elaine R. Nimmo, Jack Satsangi, Sheila A. Fisher, Alistair Forbes, Cathryn M. Lewis, Clive M. Onnie, Natalie J. Prescott, Jeremy Sanderson, Christopher G. Mathew, Jamie Barbour, M. Khalid Mohiuddin, Catherine E. Todhunter, John C. Mansfield, Tariq Ahmad, Fraser R. Cummings, Derek P. Jewell, John Webster, Morris J. Brown, G. Mark Lathrop, John Connell, Anna Dominiczak, Carolina A. Braga Marcano, Beverley Burke, Richard Dobson, Johannie Gungadoo, Kate L. Lee, Patricia B. Munroe, Stephen J. Newhouse, Abiodun Onipinla, Chris Wallace, Mingzhan Xue, Mark Caulfield, Martin Farrall, Anne Barton, Ian N. Bruce, Hannah Donovan, Steve Eyre, Paul D. Gilbert, Samantha L. Hider, Anne M. Hinks, Sally L. John, Catherine Potter, Alan J. Silman, Deborah P. M. Symmons, Wendy Thomson, Jane Worthington, David B. Dunger, Barry Widmer, Timothy M. Frayling, Rachel M. Freathy, Hana Lango, John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Andrew T. Hattersley, Graham A. Hitman, Mark Walker, Kate S. Elliott, Christopher J. Groves, Cecilia M. Lindgren, Nigel W. Rayner, Nicholas J. Timpson, Eleftheria Zeggini, Melanie NewportMelanie Newport, Giorgio Sirugo, Emily Lyons, Fredrik Vannberg, Matthew A. Brown, Jayne A. Franklyn, Joanne M. Heward, Matthew J. Simmonds, Adrian V. S. Hill, Linda A. Bradbury, Claire Farrar, Jennifer J. Pointon, Paul Wordsmith, Stephen C. L. Gough, Sheila Seal, Michael R. Stratton, Nazneen Rahman, Maria Ban, An Goris, Stephen J. Sawcer, Alistair Compston, David Conway, Muminatou Jallow, Suzannah J. Bumpstead, Amy Chaney, Kate Downes, Mohammed J. R. Ghori, Rhian Gwilliam, Michael Inouye, Andrew Keniry, Emma King, Ralph McGinnis, Simon Potter, Rathi Ravindrarajah, Pamela Whittaker, David Withers, Joanne Pereira-Gale, Ingilef B. Hallgrimsdottir, Bryan N. Howie, Zhan Su, Yik Ying Teo, Damjan Vukcevic, David Bentley
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 similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 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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