부산대학교 도서관

Keywords multiple sclerosis; genetic risk; transcriptional pause release; outside variants; cell type; oligodendrocytes; remyelination; epigenomics; GWAS; population genetics Highlights * SNPs that physically interact with a shared target gene often alter MS genetic risk * Outside variant approach predicts pathogenic cell type for individual disease alleles * A subset of MS risk SNPs alter oligodendrocyte-intrinsic cell functions * Dysregulation of RNAPII release confers MS risk and blocks oligodendrocyte maturation Summary Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. Video Abstract Display Omitted