The genetic architecture of multiple sclerosis in 2026: From susceptibility to disease progression

The genetics of multiple sclerosis (MS) has advanced dramatically through the combined impact of high-throughput genotyping, large biobank resources, worldwide collaborations, and powerful computational analyses. Over the past two decades, genome-wide association studies (GWAS) have significantly reshaped our understanding of the genetic architecture of complex multifactorial diseases such as MS. The number of MS susceptibility-associated genomic regions is now more than 200, underscoring its highly polygenic nature. Within the major histocompatibility complex (MHC), the HLA-DRB1*15:01 allele and its extended haplotypes remain the most robust and reproducible risk factors. This historical association reflects a long-standing link between antigen presentation, immune regulation, and central nervous system autoimmunity. Beyond the MHC, common non-HLA loci implicate a wide network of immune pathways involving T-cell and B-cell activation, cytokine signaling, and antigen presentation. Moreover, rare variant analyses and family-based designs, although limited in power, have uncovered additional susceptibility genes, such as PRF1, CYP27B1, and NLRP1, shedding light on distinct mechanisms of immune modulation and metabolic regulation. The step forward will be now to explore diverse genetic ancestry populations, bearing differences in risk allele frequencies; multi-ethnic and family-based designs are needed to disentangle true genetic effects from environmental confounders. In parallel, progress has been made toward MS progression, as variants potentially influencing disability accumulation and neurodegeneration were identified. These findings have deepened our understanding of MS pathophysiology. They now provide a foundation for future integrative models that combine genetics, environment, and multi-omics data to elucidate disease heterogeneity and guide personalized therapeutic strategies.