EVIDENCE FOR GENETIC-BASIS OF MULTIPLE-SCLEROSIS

Background Increased familial risks in multiple sclerosis (MS) range f rom 300-fold for monozygotic twins to 20-40-fold for biological first- degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the co ntributions of genes and environment is to study half-sibs. Methods In a Canadian population-based sample of 16 000 is MS cases seen at 14 r egional MS clinics one half-sib (or more) was reported by 939 index ca ses. By interview we elicited information on family structure and an i llness in half-sibs and any full brothers or sisters. Findings The age -adjusted MS rate in the 1839 half-sibs of these index cases was 1.32% compared with 3.46% far the 1395 full sibs of the same cases (p<0.001 ; likelihood ratio test), There were no significant differences in ris k for maternal versus paternal half-sibs (1.42% vs 1.19%) or for those raised together versus those raised apart from the index case (1.17% vs 1.47%). Interpretation Besides demonstrating the power and the feas iblity of using half-sib studies to throw light on the aetiology of co mplex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as int rauterine and perinatal factors, breastfeeding, and genomic imprinting ) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rat es) lowers the risk of MS by a factor of 2.62, an observation consiste nt with a polygenic hypothesis.