The genetic epidemiology of multiple sclerosis

Epidemiological studies have implicated an interplay between genetic and en vironmental factors in the aetiology of multiple sclerosis (MS). There is a familial recurrence rate of approximately 15%. Metaanalysis of the recurre nce risk shows that the rate is highest overall for siblings, then parents and children, with lower rates in second- and third-degree relatives. Recur rence is highest for monozygotic twins. Conversely, the frequency in adopte es is similar to the population lifetime risk. The age-adjusted risk for ha lf siblings is also less than for full siblings. Recurrence is higher in th e children of conjugal pairs with MS than the offspring of single affecteds . These classical genetic observations suggest that MS is a complex trait i n which susceptibility is determined by several genes acting independently or epistatically. Comparisons between co-affected sibling pairs provide no evidence for correlation with age or year at onset and mode of presentation or disability. Thus far, the identification of susceptibility genes has pr oved elusive but genetic strategies are now in place which should illuminat e the problem. The main dividend will be an improved understanding of the p athogenesis. To date, population studies have demonstrated an association b etween the class II major histocompatibility complex (MHC) alleles DR15 and DQ6 and their corresponding genotypes. An association with DR4, with or wi thout the primary DR15 link, is seen in some Mediterranean populations. Can didate gene approaches have otherwise proved unrewarding. Four groups of in vestigators have undertaken a systematic search of the genome. In common wi th most other complex traits, no major susceptibility gene has been identif ied but regions of interest have been provisionally identified. These genet ic analyses are predicated on the assumption that MS is one disease. Genoty pic and phenotypic analyses are beginning to question this assumption. A ma jor part of future studies in the genetics of MS will be to resolve the que stion of disease heterogeneity.