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

Wellcome Trust Case Control Consortium; 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 Mathew; Marcus 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; Craig Mowat

doi:10.1038/ng.2435

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

Wellcome Trust Case Control Consortium
, 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 Mathew, Marcus 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 (Lead / Corresponding author), Craig Mowat (Research group member)

Research output: Contribution to journal › Article › peer-review

379 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 language	English
Pages (from-to)	1294-1301
Number of pages	8
Journal	Nature Genetics
Volume	44
Issue number	12
Early online date	28 Oct 2012
DOIs	https://doi.org/10.1038/ng.2435
Publication status	Published - Dec 2012

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Genetics

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10.1038/ng.2435

Cite this

Wellcome Trust Case Control Consortium, Maller, J. B., McVean, G., Byrnes, J., Vukcevic, D., Palin, K., Su, Z., Howson, J. M. M., Auton, A., Myers, S., Morris, A., Pirinen, M., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Hall, A. S., Hattersley, A. T., ... Mowat, C. (2012). Bayesian refinement of association signals for 14 loci in 3 common diseases. Nature Genetics, 44(12), 1294-1301. https://doi.org/10.1038/ng.2435

@article{d337f996a0704954a7812e5f6d8917fa,

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.",

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

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doi = "10.1038/ng.2435",

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Wellcome Trust Case Control Consortium, Maller, JB, McVean, G, Byrnes, J, Vukcevic, D, Palin, K, Su, Z, Howson, JMM, Auton, A, Myers, S, Morris, A, Pirinen, M, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Craddock, N, Hurles, M, Ouwehand, W, Parkes, M, Rahman, N, Duncanson, A, Todd, JA, Kwiatkowski, DP, Samani, NJ, Gough, SCL, McCarthy, MI, Deloukas, P, Donnelly, P & Mowat, C 2012, 'Bayesian refinement of association signals for 14 loci in 3 common diseases', Nature Genetics, vol. 44, no. 12, pp. 1294-1301. https://doi.org/10.1038/ng.2435

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T1 - Bayesian refinement of association signals for 14 loci in 3 common diseases

AU - Wellcome Trust Case Control Consortium

AU - Maller, Julian B.

AU - McVean, Gilean

AU - Byrnes, Jake

AU - Vukcevic, Damjan

AU - Palin, Kimmo

AU - Su, Zhan

AU - Howson, Joanna M M

AU - Auton, Adam

AU - Myers, Simon

AU - Morris, Andrew

AU - Pirinen, Matti

AU - Brown, Matthew A

AU - Burton, Paul R

AU - Caulfield, Mark J

AU - Compston, Alastair

AU - Farrall, Martin

AU - Hall, Alistair S

AU - Hattersley, Andrew T

AU - Hill, Adrian V S

AU - Mathew, Christopher G

AU - Pembrey, Marcus

AU - Satsangi, Jack

AU - Stratton, Michael R.

AU - Worthington, Jane

AU - Craddock, Nick

AU - Hurles, Matthew

AU - Ouwehand, Willem

AU - Parkes, Miles

AU - Rahman, Nazneen

AU - Duncanson, Audrey

AU - Todd, John A.

AU - Kwiatkowski, Dominic P.

AU - Samani, Nilesh J.

AU - Gough, Stephen C.L.

AU - McCarthy, Mark I.

AU - Deloukas, Panagiotis

AU - Donnelly, Peter

A2 - Mowat, Craig

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

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DO - 10.1038/ng.2435

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SN - 1061-4036

VL - 44

SP - 1294

EP - 1301

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

Abstract

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