MS SNPs regulation in oligodendroglia
Multiple sclerosis (MS) is a neuroinflammatory disease where a large number of non-coding single nucleotide polymorphisms (SNPs) have been associated with risk/susceptibility and severity. Immune cells have been suggested as the main functional effector cell types of these common variants. Here, we identify 76 MS-associated SNPs whose loci present accessible chromatin in homeostatic and diseased oligodendroglia (OLG), including oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (MOLs). By applying high-throughput functional genomics, we found that a subset of these SNPs lead to variant- and cell-specific regulatory effects in human induced pluripotent stem cell-derived oligodendroglia. Phenotypic profiling of these variants indicated that rs483180:PHGDH interfered with human OPC proliferation via long-range chromatin interactions with S100A6 locus, while variants at rs2248137:CYP24A1 impaired oligodendrocyte differentiation by regulating BCAS1 expression. In addition, variants at rs1415069:DIPK1A enhanced secretion of the cytokine CCL2 by oligodendroglia, suggesting that these variants might be implicated in OLG-driven immune cell recruitment in MS. These findings place oligodendroglia as important drivers of MS pathogenesis through the orchestration of their core functionality by MS risk non-coding variants.