title: Dissection of a Complex Disease Susceptibility Region Using a Bayesian Stochastic Search Approach to Fine Mapping.
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.
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Marcin L
authors.initials: ML
authors.lastname: Pekalski
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Burren
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Arcadio Rubio
authors.initials: AR
authors.lastname: García
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Centre for Biostatistics Institute of Population Health, The University of Manchester Manchester, United Kingdom.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.affiliation: University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Richardson
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D015810:Linkage Disequilibrium; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013269:Stochastic Processes
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit