Multiple sclerosis (MS) is a prevalent demyelinating disease that primarily affects young adults. Within the realm of MS patients, the extent of disease severity and progression differs greatly across individuals. Studies conducted on post-mortem tissue samples have characterized complex lesion types that diverge significantly on the composition of oligodendrocyte (OLG) lineage cells and their degrees of remyelination, both across different individuals and within each MS patient1. To date, the intrinsic genetic factors that potentially impact OLG-mediated de- and re-myelination in MS lesions, with far-reaching implications for the clinical disease trajectory, remain inadequately understood. Given the expansive genome wide association studies (GWAS) identifying potential single nucleotide polymorphisms (SNPs) and variants in relation to MS susceptibility and severity2,3, together with the delineation of OLG heterogeneities through a genomic-transcriptomic-epigenomic axis, we have identified 42 MS-associated SNP candidates that are transcriptionally accessible across the OLG-lineage. By applying a single-cell resolution CRISPRi/a screen4 on selected SNPs in human induced pluripotent stem cell (hiPSC)-derived OLGs, whether exposed to interferon-induced inflammation challenges or not, our objective is to assess the impact of these specific SNPs on OLG transcriptome profiles. Through this analysis, we aim to elucidate the potential mechanistic implications of these individual SNPs within the framework of MS.By delving into the link between disease-associated SNPs with OLG cell type and subtype specific functions, this project will provide valuable insights into MS-related genetic risks. These findings have the potential to advance diagnostic and therapeutic approaches in MS research.