MS etiology is multifaceted, but genetic susceptibility clearly plays a role as monozygotic (MZ) twins display a 20-35% MS concordance rate. Moreover, MS susceptibility has already been associated with a considerable number of single-nucleotide polymorphisms (SNPs).

QTL analysis revealed 5866 genome-wide significant associations (p<5e-8) corresponding to 57 discrete FACS phenotypes and approximately 3240 genes. The 24 most supported FACS phenotypes associated with MHCII-and MCAM populations, as well as terminally differentiated T effector phenotypes. In addition, our approach confirmed known associations with MS susceptibility (TYK2) and inflammatory biomarkers (HBE1, HBG2). Next, we investigated immune cell lineage-specific MS risk variants and identified common and cell-specific biological pathways, as well as positional gene enrichment for CD4 T cell, CD8 T cell and B cell phenotypes. Finally, we evaluated the regulation of gene expression in the most supported immune cell lineage CD4 T cells and performed bulk-RNA sequencing of sorted CD4 T cells derived from 16 MS-discordant twin pairs. eQTL analysis revealed 45 independent, suggestive signals (p<1e-5), that identified candidate genes for MS susceptibility i.e. NAPG, CTNNA1 and CRLF3.