The clinical relevance of multiple sclerosis genetics: from susceptibility to disease severity and progression

Large-scale genome-wide association studies have identified hundreds of multiple sclerosis risk loci, most of which implicate immune pathways and establish multiple sclerosis as a highly polygenic, immune-mediated disease. These findings help explain why immune-modifying therapies suppress relapses and new lesion formation. However, susceptibility genetics does not adequately explain disability accumulation, variation in disease course, or treatment response. Evidence from rare-variant studies, genetic studies of disease severity and disability progression, epigenetic analyses, gene-environment studies, and Epstein-Barr virus research is beginning to extend this genetic framework from susceptibility to disease expression. Still, the direct clinical relevance of this research remains constrained by modest individual-level predictive value, underpowered studies of genetic determinants of disease severity and disability progression, complex regulatory mechanisms linking variants to function, and restricted generalisability across populations. At present, multiple sclerosis genetics is most useful for interpreting mechanisms, prioritising therapeutic targets, supporting causal inference, informing biomarker discovery, and enriching research cohorts. Future clinical value will likely depend on integrating genetic architecture with longitudinal clinical, imaging, biomarker, and multi-omic data to identify the contexts in which prevention or treatment is most likely to succeed.