Bayesian refinement of association signals for 14 loci in 3 common diseases

Julian B. Maller, Gilean McVean, Jake Byrnes, Damjan Vukcevic, Kimmo Palin, Zhan Su, Joanna M M Howson, Adam Auton, Simon Myers, Andrew Morris, Matti Pirinen, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, Alastair Compston, Martin Farrall, Alistair S. Hall, Andrew T. Hattersley, Adrian V S Hill, Christopher G. MathewMarcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Nick Craddock, Matthew Hurles, Willem Ouwehand, Miles Parkes, Nazneen Rahman, Audrey Duncanson, John A. Todd, Dominic P. Kwiatkowski, Nilesh J. Samani, Stephen C L Gough, Mark I. McCarthy, Panagiotis Deloukas, Peter Donnelly*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

244 Citations (Scopus)

Abstract

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.

Original languageEnglish
Pages (from-to)1294-1301
Number of pages8
JournalNature Genetics
Volume44
Issue number12
DOIs
Publication statusPublished - Dec 2012

Keywords

  • Bayes Theorem
  • CTLA-4 Antigen
  • Coronary Artery Disease
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinase Inhibitor p15
  • Diabetes Mellitus, Type 2
  • Genes, p16
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Graves Disease
  • Homeodomain Proteins
  • Humans
  • Polymorphism, Single Nucleotide
  • Proteins
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors

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