| Literature DB >> 32246942 |
Daniel C Factor1, Anna M Barbeau2, Kevin C Allan1, Lucille R Hu1, Mayur Madhavan1, An T Hoang2, Kathryn E A Hazel2, Parker A Hall3, Sagar Nisraiyya2, Fadi J Najm1, Tyler E Miller4, Zachary S Nevin1, Robert T Karl1, Bruna R Lima2, Yanwei Song2, Alexandra G Sibert2, Gursimran K Dhillon1, Christina Volsko5, Cynthia F Bartels1, Drew J Adams1, Ranjan Dutta5, Michael D Gallagher2, William Phu3, Alexey Kozlenkov6, Stella Dracheva6, Peter C Scacheri7, Paul J Tesar1, Olivia Corradin8.
Abstract
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.Entities:
Keywords: GWAS; cell type; epigenomics; genetic risk; multiple sclerosis; oligodendrocytes; outside variants; population genetics; remyelination; transcriptional pause release
Mesh：
Year: 2020 PMID： 32246942 PMCID： PMC7426147 DOI： 10.1016/j.cell.2020.03.002
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582