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

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. SpencerMartin 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, Biol RA Genet & Genom Study Syndicate, Wellcome Trust Case Control Consortium, Breast Canc Susceptib Collaborat

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7045 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)661-678
Number of pages18
JournalNature
Volume447
Issue number7145
DOIs
Publication statusPublished - 7 Jun 2007

Keywords

  • single-nucleotide polymorphisms
  • coronary-artery-disease
  • mitochondrial c-1-tetrahydrofolate synthase
  • lymphoid tyrosine phosphatase
  • rheumatoid-arthritis families
  • inflammatory-bowel-disease
  • multilocus genotype data
  • affected sibling pairs
  • type-1 diabetes locus
  • bipolar disorder

Cite this

Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., Ouwehand, W. H., Samani, N. J., Todd, J. A., Donnelly, P., Barrett, J. C., Davison, D., Easton, D., Evans, D., Leung, H-T., Marchini, J. L., Morris, A. P., ... Biol RA Genet & Genom Study Syndicate, Wellcome Trust Case Control Consortium, Breast Canc Susceptib Collaborat (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447(7145), 661-678. https://doi.org/10.1038/nature05911