Multiple Sclerosis Polygenic Risk Is Not Enriched in Three Multicase Families in Comparison to Population-Based Cases

Multiple sclerosis (MS) is a complex neurological and autoimmune disease with an established genetic component. Families with multiple cases of MS are rare but do occur. We hypothesised that multicase families may have a heightened polygenic risk for MS. In this work, we have determined whether polygenic risk for MS is enriched in multicase families in comparison to a case-control cohort. Using the findings from the largest MS genome-wide association study, we calculated a weighted polygenic risk score (wPRS) for MS. We applied this wPRS to study a population-based MS case-control cohort (3,252 people with MS and 5,725 controls) and three multicase MS families (9 individuals with MS, 10 unaffected family members). For both the population-based cohort and the three families, 167 of the 233 known genome-wide significant MS-associated variants were identified and used to calculate the wPRS. Within the population-based cohort, the wPRS was significantly higher in MS cases than controls (P = 2.2 × 10⁻¹⁶). The wPRS of familial MS cases was not significantly different to population-based MS cases (P > 0.05). Both affected and unaffected MS family members had higher wPRS than population controls. MS families have a higher polygenic risk for MS, but this did not differ to the polygenic risk of population-based MS cases. Only one family carried the established HLA-DRB1 15:01 MS risk allele, which was present in both affected and unaffected family members. Across families, unaffected family members had an elevated polygenic risk in comparison to population controls indicating that a higher polygenic risk does not fully explain the clustering of MS in families.