Genetic Risk in Multiple Sclerosis: Susceptibility, Modifiers and Unresolved Questions.

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterised by inflammation, demyelination and neurodegeneration. The aetiology of MS is complex, arising from interactions among genetic susceptibility, environmental exposures and stochastic immune processes. Over the past 2 decades, large-scale genomic studies have fundamentally shaped our understanding of MS pathogenesis, establishing disease risk as highly polygenic and predominantly driven by immune regulatory mechanisms. Genome-wide association studies (GWAS) have identified 233 common susceptibility variants, including 201 outside the major histocompatibility complex (MHC), with the strongest effects localised to the MHC, particularly HLA-DRB1*15:01. These genetic associations implicate pathways involved in antigen presentation, T- and B-cell activation, cytokine signalling and innate immune responses. Family-based studies have identified putative rare susceptibility variants, but no single gene has been confirmed to cause MS. However, genetic risk alone is insufficient to cause disease, and gene-environment interactions, most notably with Epstein-Barr virus infection, vitamin D insufficiency, obesity, smoking and sex-specific hormonal factors, are critical determinants of disease manifestation. Here, we synthesise current evidence on the genetic architecture of MS, the biological mechanisms linking genetic risk to disease susceptibility and the ways in which genetic factors intersect with environmental exposures to shape clinical outcomes. We further review emerging data on the influence of genetic variation on disease course, prognosis and treatment response. Finally, we discuss unmet needs and future directions, including the role that family studies can play in further informing our understanding of MS pathology, the need for ancestry-diverse studies, multi-omics integration and the translation of genetic insights into clinical care.