[The genetic profile of multiple sclerosis: risk genes and the "dark matter"]

Multiple sclerosis (MS) is a genetically complex disease caused by the interplay of genetic and environmental factors. While it shows substantial familial accumulation, there is no evidence for typical Mendelian transmission within families. Instead, MS risk is likely governed by dozens to hundreds of genetic variants, which can also be present in the general population. The strongest genetic risk factor for MS was identified 40 years ago and lies within the HLA locus. It increases the risk of developing MS by two- to threefold. Within the last few years, genome-wide association studies (GWAS) have led to the identification of nearly 60 additional genetic risk loci. Each of these loci yields a modest to moderate risk increase (odds ratios of 1.1-1.3). Even in combination, however, the currently known risk variants merely account for a small fraction of the disease's heritability. It is likely that a major fraction of genetic MS risk that cannot be explained by GWAS, sometimes termed the "dark matter" of GWAS, is caused by other factors, such as structural variations of the genome, rare sequence variants, or inherited epigenetic modifications.