Abstract Multiple sclerosis (MS) is an immune-mediated, long-term disease of the central nervous system and a leading cause of neurological disability. Despite rapid progress in genome-wide association studies leading to the identification of 233 genetic risk loci for MS susceptibility, the genetic determinants of MS severity remain unclear. To date, only one genome-wide significant locus has been reliably linked to MS severity. Moreover, several observational and Mendelian randomisation (MR) studies have investigated the relationship between environmental and lifestyle factors and MS severity, but the results have been inconsistent. This review summarises the current evidence on both genetic and nongenetic risk factors for MS severity. It also explores potential explanations for the lack of genetic variants associated with MS severity and discusses the methodological challenges that underlie the contradictory findings between observational studies and MR studies. Finally, his review emphasises the biological significance and potential clinical relevance of the recently discovered MS severity locus in the DYSF–ZNF638 region and considers evidence for epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs, that may play key roles in modulating disease severity.
Mona M. Almramhi (Mon,) studied this question.