Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets

Abstract

Abstract Background Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. Results We utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to Th17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. Conclusions Overall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.