Abstract
Multiple sclerosis (MS) is an immune-mediated, inflammatory, and neurodegenerative disease of the central nervous system with a complex, multifactorial etiology. Familial aggregation, along with a higher concordance rate in monozygotic than dizygotic twins, supports a significant, albeit non-Mendelian, genetic contribution to MS susceptibility. The strongest genetic association involves the human leukocyte antigen (HLA) region, particularly HLA-DRB1*15:01, while genome-wide association studies have identified over 200 additional susceptibility signals, most of which implicate immune regulation and, increasingly, microglial biology. These genetic effects are not sufficient to cause disease. Environmental and lifestyle factors, including Epstein-Barr virus infection, vitamin D deficiency, limited exposure to ultraviolet B radiation, cigarette smoking, and adolescent obesity, act as complementary risk modifiers. Biological factors related to sex, gut microbiota, epigenetic regulation, and gene-environment interactions further refine individual susceptibility. Familial MS should therefore be viewed as an enriched model of polygenic susceptibility interacting with shared environmental factors, rather than as a distinct entity linked to a single gene. Increasing evidence suggests that pathological processes associated with MS may begin many years before the first clinical symptoms. Projects such as the Genes and Environment in Multiple Sclerosis (GEMS) project and the development of integrated genetic and environmental risk scores may enable risk stratification among first-degree relatives and other high-risk groups. This review summarizes the current evidence on the familial occurrence of MS, highlights the interplay of inherited and acquired risk factors, and discusses implications for early detection and future primary prevention strategies.