Genetics of Multiple Sclerosis

Evidence for a genetic component in multiple sclerosis (MS) is found in the clustering of affected individuals in families and differences in disease prevalence among different ancestral groups, regardless of geographic location. Genes encoding antigen-presenting molecules within the human leukocyte antigen region in chromosome 6p21 account for the largest part of the genetic risk for MS; the primary signal within the major histocompatibility complex maps to the HLA-DRB1 gene, or more specifically to the DRB1?15:01 allele. The genome-wide association study approach has been highly successful in uncovering non-HLA DNA variants influencing susceptibility. Overall, the results are consistent with a polygenic model of inheritance. The data also support the long-held view that MS susceptibility rests on the action of polymorphisms common in the population. Their incomplete penetrance and moderate individual effects reflect most likely interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. For the first time we are in a position to define the full array of genes, pathways, and genetic networks operating in MS. In addition to gene identification, these studies will drive a forceful paradigm shift in the study of MS by allowing a more refined mechanistic representation of disease pathogenesis. Equally important, this information may reveal novel targets for therapy, prevention, and repair.