Contrasting genetic architectures of multiple sclerosis susceptibility and outcome phenotypes

Abstract

Multiple sclerosis (MS) is characterized by substantial clinical heterogeneity, yet the factors governing long-term outcomes remain poorly understood. Over the past two decades, genome-wide association studies have identified an increasing number of genetic variants influencing MS susceptibility, predominantly implicating immune pathways. Whether these same variants also shape disease course after onset is a question with direct implications for risk prediction, causal inference, and drug development in patients with established disease. This review examines the relationship between MS susceptibility genetics and disease outcomes, synthesizes emerging efforts to identify genetic determinants of severity, neuroimaging phenotypes, and treatment response, and considers how these findings inform our understanding of the mechanisms driving disease heterogeneity.