title: Bayesian refinement of association signals for 14 loci in 3 common diseases.
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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Julian B
authors.initials: JB
authors.lastname: Maller
authors.forename: Gilean
authors.initials: G
authors.lastname: McVean
authors.forename: Jake
authors.initials: J
authors.lastname: Byrnes
authors.forename: Damjan
authors.initials: D
authors.lastname: Vukcevic
authors.forename: Kimmo
authors.initials: K
authors.lastname: Palin
authors.forename: Zhan
authors.initials: Z
authors.lastname: Su
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.forename: Adam
authors.initials: A
authors.lastname: Auton
authors.forename: Simon
authors.initials: S
authors.lastname: Myers
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Hall
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Marcus
authors.initials: M
authors.lastname: Pembrey
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Nick
authors.initials: N
authors.lastname: Craddock
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.forename: Willem
authors.initials: W
authors.lastname: Ouwehand
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
authors.forename: Audrey
authors.initials: A
authors.lastname: Duncanson
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Stephen C L
authors.initials: SC
authors.lastname: Gough
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Deloukas
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D001499:Bayes Theorem; D060908:CTLA-4 Antigen / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D019942:Genes, p16; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D012359:tRNA Methyltransferases
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D011506:Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human