Year: 2011
Type: review
Abstract: OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
Source: Annals of Neurology
DOI: 10.1002/ana.22609
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: National Multiple Sclerosis Society, John T. Reid Charitable Trusts, Wellcome Trust, National Institute for Health and Care Research, Multiple Sclerosis Australia, Trish Multiple Sclerosis Research Foundation, National Institutes of Health, Medical Research Council, Australian Research Council, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: G1137313802, The Role of Rare Variants in Multiple Sclerosis Risk, G2064885621, DIAGNOSTIC CENTER FOR LINKAGE STUDIES OF SCHIZOPHRENIA, G2824707892, Molecular Genetics of Schizophrenia, G3349769430, LINKAGE STUDIES OF SCHIZOPHRENIA, Molecular Genetics of Schizophrenia, Molecular Genetics of Schizophrenia, Molecular Genetics of Schizophrenia, Genome-Wide Association Study of Schizophrenia, Molecular Genetics of Schizophrenia, DIAGNOSTIC CENTER FOR SCHIZOPHRENIA LINKAGE STUDIES, A Genome-Wide Association Study of Schizophrenia, G5502349062, G5568298347, A national DNA control series for genetic case-control studies based on the British 1958 birth cohort, Molecular Genetics of Schizophrenia, Molecular Genetics of Schizophrenia, G6661414329, Exploring the consequences of the TNFRSF1A susceptibility allele for MS, Molecular Genetics of Schizophrenia, Molecular Genetics of Schizophrenia, Genome-wide Association Study of Schizophrenia, Improving genotype call accuracy, G7627314639, Identifying genes that influence clinical course and susceptibility in multiple sclerosis, Molecular Genetics of Schizophrenia, NIHR Senior Investigator Award, Costimulatory Mechanisms of Autoimmunity
OpenAlex ID: W2110228129