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

Authors
Paul Burton,Andrew Paterson
Peter Donnelly,Nick Craddock,Panos Deloukas,Audrey Duncanson,Dominic Kwiatkowski,Mark McCarthy,Willem Ouwehand,Nilesh Samani,John Todd,Jeffrey Barrett,Dan Davison,Douglas Easton,David Evans,H.T. Leung,Jonathan Marchini,Andrew Hattersley,Chris Spencer,Martin Tobin,Antony Attwood,James Boorman,Barbara Cant,Ursula Everson,Judith Hussey,Kerstin Koch,Sarah Nutland,C Prowse,Helen Stevens,Niall Taylor,G. Walters,Neil Walker,Nicholas Watkins,Thilo Winzer,Richard Jones,Wendy McArdle,Susan Ring,David Strachan,Marcus Pembrey,Gerome Breen,David Collier,Sian Caesar,Katherine Gordon‐Smith,Sheikh Alam,Christine Fraser,Detelina Grozeva,Marian Hamshere,Lisa Jones,George Kirov,Valentina Escott‐Price,Michael O’Donovan,Peter Holmans,Richard Williamson,Allan Young,I. Ferrier,Stephen Ball,Anthony Balmforth,Jennifer Barrett,D. Bishop,Mark Iles,Azhar Maqbool,Nadira Yuldasheva,Alistair Hall,Richard Dixon,John Thompson,Mark Tremelling,Miles Parkes,Hazel Drummond,Charlie Lees,Massimo Mangino,Suzanne Stevens,Sheila Fisher,Alastair Forbes,Cathryn Lewis,Clive Onnie,Natalie Prescott,Jeremy Sanderson,Christopher Mathew,Mohamed Mohiuddin,Catherine Todhunter,John Mansfield,D Jewell,Matthew Brown,G. Lathrop,John Connell,Anna Dominiczak,Casandra Marcano,Beverley Burke,Richard Dobson,Fraser Cummings,Leena Peltonen,Patricia Munroe,Stephen Newhouse,Abiodun Onipinla,Chris Wallace,Mingzhan Xue,Mark Caulfield,Martin Farrall,Anne Barton,Stephen Epstein,Sally John,Alan Silman,Deborah Symmons,Wendy Thomson,David Dunger,Ian Bruce,Timothy Frayling,Hana Allen,Samantha Hider,Beverley Shields,Michael Weedon,Graham Hitman,Mark Walker,Cecilia Lindgren,Nicholas Timpson,Eleftheria Zeggini,Melanie Newport,Giorgio Sirugo,Emily Lyons,Fredrik Vannberg,Rachel Freathy,Claire Farrar,Jennifer Pointon,Jayne Franklyn,J. Heward,Matthew Simmonds,Stephen Gough,Michael Stratton,Nazneen Rahman,An Goris,Stephen Sawcer,A. Compston,David Conway,Muminatou Jallow,Kirk Rockett,Suzannah Bumpstead,C. Farrar,Mohammed Ghori,Rhian Gwilliam,Sarah Hunt,Michael Inouye,Emma King,Ralph McGinnis,Simon Potter,Rathi Ravindrarajah,Pamela Whittaker,Maria Ban,Leonardo Bottolo,Teresa Ferreira,Joanne Pereira-Gale,Ingileif Hallgrímsdóttir,Bryan Mowry,Zhan Su,Yik Teo,Damjan Vukcevic
+153 authors
,David Bentley
Journal
Published
Jun 6, 2007
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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 ∼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.

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