<h3>Objective:</h3> To investigate the role of known multiple sclerosis (MS)-associated genetic variants in MS familial aggregation, clinical expression, and accuracy of disease prediction in sporadic and familial cases. <h3>Methods:</h3> A total of 1,443 consecutive patients were screened for MS and familial autoimmune history in a hospital-based Italian cohort. Among them, 461 sporadic and 93 familial probands were genotyped for 107 MS-associated polymorphisms. Their effect sizes were combined to calculate the weighted genetic risk score (wGRS). <h3>Results:</h3> Family history of MS was reported by 17.2% of probands, and 33.8% reported a familial autoimmune disorder, with autoimmune thyroiditis and psoriasis being the most frequent. No difference in wGRS was observed between sporadic and familial MS cases. In contrast, a lower wGRS was observed in probands with greater familial aggregation (&gt;1 first-degree relative or &gt;2 relatives with MS) (<i>p</i> = 0.03). Also, female probands of familial cases with greater familial aggregation had a lower wGRS than sporadic cases (<i>p</i> = 0.0009) and male probands of familial cases (<i>p</i> = 0.04). An inverse correlation between wGRS and age at onset was observed (<i>p</i> = 0.05). The predictive performance of the genetic model including all known MS variants was modest but greater in sporadic vs familial cases (area under the curve = 0.63 and 0.57). <h3>Conclusions:</h3> Additional variants outside the known MS-associated loci, rare variants, and/or environmental factors may explain disease occurrence within families; in females, hormonal and epigenetic factors probably have a predominant role in explaining familial aggregation. The inclusion of these additional factors in future versions of aggregated genetic measures could improve their predictive ability.

Impact of MS genetic loci on familial aggregation, clinical phenotype, and disease prediction