Genetic susceptibility to multiple sclerosis: a review.

We review evidence on genetic susceptibility to multiple sclerosis provided by studies of family resemblance, migrants, twins, HLA-associations, and segregation and linkage analyses. The higher concordance rate in MZ than DZ twins and the increasing prevalence with increasing degree of kinship to propositi suggest that genetic factors are involved in the aetiology of MS. Nonetheless, the low overall twin concordance rates, the increased prevalence of MS in DZ twins over siblings, and the weight of evidence from migrant studies strongly suggest the involvement of environmental factors as well. These results can be reconciled by hypothesizing an MS susceptibility gene with reduced penetrance, where full phenotypic expression depends on critical environmental exposures. The location of this gene in or near the HLA region is suggested by the reports of HLA-MS associations and is supported by results of formal linkage analyses. Two general hypotheses have emerged. One involves loose linkage with no heterogeneity while the other involves very tight linkage and substantial heterogeneity, ie no linkage in 25% of the pedigrees. Since the MS gene is probably not a recent mutation, the hypothesis of loose linkage requires one to postulate intense selection to maintain linkage disequilibrium. It is primarily because of this intense selection that we currently favour the hypothesis of tight linkage with heterogeneity over any single-gene hypothesis involving loose linkage, given our present biological knowledge. Areas for future research are suggested.