Susceptibility Genes for Multiple Sclerosis Identifed in a Gene-Based Genome-Wide Association Study
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Background and Purpose Multiple sclerosis (MS) is a demyelinating and infammatory disease of the central nervous system. Te aim of this study was to identify more genes associated with MS. Methods Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets. Results A total of 58 genes was identifed, including 20 “novel” genes signifcantly associated with MS (p<1.40×10-4). In the replication study, 44 of the 58 identifed genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identifed genes exhibited diferential expressions in MS-related cells. Tus, 15 novel genes were supported by replicated association and/or diferential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both. Conclusion zTe results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. Te novel genes identifed herein may provide new insights into the molecular genetic mechanisms underlying MS.
Abstract
Background and Purpose Multiple sclerosis (MS) is a demyelinating and infammatory disease of the central nervous system. Te aim of this study was to identify more genes associated with MS. Methods Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets. Results A total of 58 genes was identifed, including 20 “novel” genes signifcantly associated with MS (p<1.40×10-4). In the replication study, 44 of the 58 identifed genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identifed genes exhibited diferential expressions in MS-related cells. Tus, 15 novel genes were supported by replicated association and/or diferential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both. Conclusion zTe results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. Te novel genes identifed herein may provide new insights into the molecular genetic mechanisms underlying MS.
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