Effect of age at onset and parental disease status on sibling risks for MS.

MS is believed to be a complex trait determined by genetic and nongenetic factors. Data suggest that MS susceptibility and age at onset are each, at least to some extent, under genetic control. The present study carefully examined five covariates (sex of the index case, sex of the sibling, birth cohort of the sibling [< or = 1919, 1920 to 1939, > or = 1940], age of MS onset in the index patient (< or = 20 years, 21 to 30 years, 31 to 40 years, > 40 years), and MS disease status of the parents [i.e., MS present in one parent or no parent with MS]) that may influence the familial risk of MS in a large cohort of 1,896 MS patients and 8,878 of their first-degree relatives. Of these, sex of the sibling, parental MS status, and index patient onset age were the important factors influencing MS risks to siblings. The results of this study are (1) the index-patient-onset-age effect suggests that individuals with a greater genetic loading (i.e., a greater contribution of susceptibility alleles) have an earlier age at onset and (2) genetic loading is substantially increased in individuals with an affected parent. These data are important both for genetic counseling and gene identification studies.