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Dissection of a complex disease susceptibility region using a Bayesian stochastic search approach to fine mapping

View ORCID ProfileChris Wallace, View ORCID ProfileAntony J Cutler, View ORCID ProfileNikolas Pontikos, View ORCID ProfileMarcin L Pekalski, View ORCID ProfileOliver S Burren, View ORCID ProfileJason D Cooper, View ORCID ProfileArcadio Rubio García, View ORCID ProfileRicardo C Ferreira, View ORCID ProfileHui Guo, View ORCID ProfileNeil M Walker, View ORCID ProfileDeborah J Smyth, View ORCID ProfileStephen S Rich, View ORCID ProfileSuna Onengut-Gumuscu, View ORCID ProfileStephen J Sawcer, View ORCID ProfileMaria Ban, View ORCID ProfileSylvia Richardson, View ORCID ProfileJohn A Todd, View ORCID ProfileLinda S Wicker
doi: https://doi.org/10.1101/015164
Chris Wallace
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
2MRC Biostatistics Unit, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK
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Antony J Cutler
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Nikolas Pontikos
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Marcin L Pekalski
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Oliver S Burren
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Jason D Cooper
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Arcadio Rubio García
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Ricardo C Ferreira
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Hui Guo
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
4Centre for Biostatistics Institute of Population Health The University of Manchester Room 1.308, Jean McFarlane Building Oxford Road Manchester M13 9PL
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Neil M Walker
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Deborah J Smyth
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Stephen S Rich
5Center for Public Health Genomics, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA
6Department of Medicine, Division of Endocrinology, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA
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Suna Onengut-Gumuscu
5Center for Public Health Genomics, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA
7Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA
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Stephen J Sawcer
8University of Cambridge, Department of Clinical Neurosciences, Box 165, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK
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Maria Ban
8University of Cambridge, Department of Clinical Neurosciences, Box 165, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK
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Sylvia Richardson
2MRC Biostatistics Unit, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK
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John A Todd
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Linda S Wicker
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Research Campus, Cambridge, CB2 0XY, UK
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Abstract

Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1D associated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r2 ≃ 0.3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4+ T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data.

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Posted June 10, 2015.
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Dissection of a complex disease susceptibility region using a Bayesian stochastic search approach to fine mapping
Chris Wallace, Antony J Cutler, Nikolas Pontikos, Marcin L Pekalski, Oliver S Burren, Jason D Cooper, Arcadio Rubio García, Ricardo C Ferreira, Hui Guo, Neil M Walker, Deborah J Smyth, Stephen S Rich, Suna Onengut-Gumuscu, Stephen J Sawcer, Maria Ban, Sylvia Richardson, John A Todd, Linda S Wicker
bioRxiv 015164; doi: https://doi.org/10.1101/015164
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Dissection of a complex disease susceptibility region using a Bayesian stochastic search approach to fine mapping
Chris Wallace, Antony J Cutler, Nikolas Pontikos, Marcin L Pekalski, Oliver S Burren, Jason D Cooper, Arcadio Rubio García, Ricardo C Ferreira, Hui Guo, Neil M Walker, Deborah J Smyth, Stephen S Rich, Suna Onengut-Gumuscu, Stephen J Sawcer, Maria Ban, Sylvia Richardson, John A Todd, Linda S Wicker
bioRxiv 015164; doi: https://doi.org/10.1101/015164

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