Multiple sclerosis (MS) is a complex demyelinating disorder of the central nervous system in which common variants explain only a portion of the disease heritability. The purpose of this research was to elucidate the contribution of rare, predicted pathogenic (RPP) variants in the aetiology of familial MS (FMS). We analysed the burden of RPP variants in genes, associated with MS via genome-wide association studies (GWAS), familial MS studies and multi-omic integration. 87 FMS cases, 128 sporadic MS (SMS) cases and 3866 controls were included in the study. The RPP burden analysis was performed on both the cohort and gene level. We also investigated possible digenic MS risk factors. At the cohort level we found an increased burden of RPP variants in the FMS cohort in genes, associated with MS via GWAS and familial MS studies. At the gene level, we identified ten burdened genes in the FMS cohort (ALPK2, AGER, ANKRD55, CUL9, INTS8, IQCB1, JADE2, MALT1, MTMR7 and SMARCA4) and five burdened genes in the SMS cohort (AGER, LIMK2, NLRP3, P2RX7 and PLAU). We did not identify a burden of predicted pathogenic variant combinations (PPVCs). The results indicate that RPP variants contribute to the genetic component of FMS. The results confirm a role of RPP variants in MS genes identified via GWAS as MS risk factors, whereas some suggested monogenic candidate genes could not be validated in an independent population. The results also indicate that the multi-omic integration approach is suitable for identifying MS risk factors, which is supported by their burden of RPP variants and biological functions. However, the digenic risk factor analysis results suggest limitations of existing methods for identifying digenic MS risk factors.
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