Modelling genetic susceptibility to multiple sclerosis with family data

A genetic contribution to susceptibility is well established in multiple sclerosis (MS) and 57 associated genetic loci have been identified. We have undertaken a meta-analysis of familial risk studies with the aims of providing definitive figures for risks to relatives, performing a segregation analysis and estimating the proportion of the overall genetic risk that currently identified genes represent. We have used standard methods of meta-analysis combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. The overall recurrence risk for monozygotic twins was 18.2% and for siblings 2.7%. The recurrence risk for dizygotic twins was significantly higher than for siblings. The overall estimate of sibling relative risk (λ_S) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for λ_S was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect with many loci of small effect. The estimated contribution of the 57 known MS loci is 18-24% of λ_S. This meta-analysis supports the notion of MS being in part the result of multiple genetic susceptibility factors and environmental factors.