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

被引：336

作者：

Maller, Julian B. ^{[1
,2
]}

McVean, Gilean ^{[1
,2
]}

Byrnes, Jake ^{[1
]}

Vukcevic, Damjan ^{[1
]}

Palin, Kimmo ^{[3
]}

Su, Zhan ^{[1
]}

Howson, Joanna M. M. ^{[4
,5
]}

Auton, Adam ^{[1
]}

Myers, Simon ^{[1
,2
]}

Morris, Andrew ^{[1
]}

Pirinen, Matti ^{[1
]}

Brown, Matthew A. ^{[6
,7
]}

Burton, Paul R. ^{[8
,9
]}

Caulfield, Mark J. ^{[10
]}

Compston, Alastair ^{[11
]}

Farrall, Martin ^{[1
]}

Hall, Alistair S. ^{[12
]}

Hattersley, Andrew T. ^{[13
]}

Hill, Adrian V. S. ^{[1
]}

Mathew, Christopher G. ^{[14
]}

Pembrey, Marcus ^{[15
]}

Satsangi, Jack ^{[16
]}

Stratton, Michael R. ^{[3
,17
]}

Worthington, Jane ^{[18
]}

Craddock, Nick ^{[19
]}

Hurles, Matthew ^{[3
]}

Ouwehand, Willem ^{[3
,20
,21
]}

Parkes, Miles ^{[22
]}

Rahman, Nazneen ^{[17
]}

Duncanson, Audrey ^{[23
]}

Todd, John A. ^{[5
]}

Kwiatkowski, Dominic P. ^{[1
,3
]}

Samani, Nilesh J. ^{[24
,25
]}

Gough, Stephen C. L. ^{[26
,27
]}

McCarthy, Mark I. ^{[1
,26
,27
]}

Deloukas, Panagiotis ^{[3
]}

Donnelly, Peter ^{[1
,2
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[3] Wellcome Trust Sanger Inst, Cambridge, England

[4] Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England

[5] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Cambridge, England

[6] Univ Oxford, Nuffield Orthopaed Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England

[7] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst Canc Immunol & Metab Med, Brisbane, Qld, Australia

[8] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[9] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England

[10] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol & Barts & London Genome Ctr, London, England

[11] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[12] Univ Leeds, LIGHT, MCRC, Leeds, W Yorkshire, England

[13] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

[14] Kings Coll London, Sch Med, Guys Hosp, Dept Med & Mol Genet, London WC2R 2LS, England

[15] UCL, Inst Child Hlth, Clin & Mol Genet Unit, London, England

[16] Univ Edinburgh, Western Gen Hosp, Sch Mol & Clin Med, Gastrointestinal Unit, Edinburgh, Midlothian, Scotland

[17] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England

[18] Univ Manchester, Arthritis Res UK Epidemiol Unit, Manchester, Lancs, England

[19] Cardiff Univ, Sch Med, Ctr Neuropsychiat Genet & Genom, MRC, Cardiff, S Glam, Wales

[20] Univ Cambridge, Dept Haematol, Cambridge, England

[21] Cambridge Ctr, Natl Hlth Serv Blood & Transplant, Cambridge, England

[22] Addenbrookes Hosp, Inflammatory Bowel Dis Genet Res Grp, Cambridge, England

[23] Wellcome Trust Res Labs, London, England

[24] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

[25] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res NIHR, Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England

[26] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Med, Oxford, England

[27] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

来源：

NATURE GENETICS | 2012年 / 44卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/ng.2435

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1294 / 1301

页数：8

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