title: Regulatory genomic regions active in immune cell types explain a large proportion of the genetic risk of multiple sclerosis.
abstract: There is little understanding of how genetic variants discovered in recent genome-wide association studies are involved in the pathogenesis of multiple sclerosis (MS). We aimed to investigate which chromatin states and cell types explain genetic risk in MS. We used genotype data from 1854 MS patients and 5164 controls produced by the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium. We estimated the proportion of phenotypic variance between cases and controls explained by cell-specific chromatin state and DNase I hypersensitivity sites (DHSs) using the Genome-wide Complex Trait Analysis software. A large proportion of variance was explained by single-nucleotide polymorphisms (SNPs) in strong enhancer (SE) elements of immortalized B lymphocytes (5.39%). Three independent SNPs located within SE showed suggestive evidence of association with MS: rs12928822 (odds ratio (OR)=0.81, 95% confidence interval (CI)=0.73-0.89, P=2.48E-05), rs727263 (OR=0.75, 95% CI=0.66-0.85, P=3.26E-06) and rs4674923 (OR=0.85, 95% CI=0.79-0.92, P=1.63E-05). Genetic variants located within DHSs of CD19+ B cells explained the greatest proportion of variance. Genetic variants influencing the risk of MS are located within regulatory elements active in immune cells. This study also identifies a number of immune cell types likely to be involved in the causal cascade and that carry important implications for future studies of therapeutic design.
authors: Functional Genomics Unit, Department of Physiology, Anatomy and Genetics and Medical Research Council, University of Oxford, Oxford, UK.
authors: Ramyiadarsini I
authors: RI
authors: Elangovan
authors: 1] Functional Genomics Unit, Department of Physiology, Anatomy and Genetics and Medical Research Council, University of Oxford, Oxford, UK [2] Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.
authors: Giulio
authors: G
authors: Disanto
authors: Functional Genomics Unit, Department of Physiology, Anatomy and Genetics and Medical Research Council, University of Oxford, Oxford, UK.
authors: Antonio J
authors: AJ
authors: Berlanga-Taylor
authors: 1] Functional Genomics Unit, Department of Physiology, Anatomy and Genetics and Medical Research Council, University of Oxford, Oxford, UK [2] Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.
authors: Sreeram V
authors: SV
authors: Ramagopalan
authors: Functional Genomics Unit, Department of Physiology, Anatomy and Genetics and Medical Research Council, University of Oxford, Oxford, UK.
authors: Lahiru
authors: L
authors: Handunnetthi
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002843:Chromatin / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D056945:Hep G2 Cells; D006801:Humans; D015603:Keratinocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid; D012307:Risk Factors
chemical_list: D002843:Chromatin; D003850:Deoxyribonuclease I