Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation

Abstract

Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified; however, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the presence of a higher rare risk variation burden in the families. In line with this, score distributions among affected and unaffected family members within individual families showed that known susceptibility alleles can explain disease development in some high-risk multiplex families, while in others, additional genetic contributors increase MS risk.

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

“…A limitation of these previous studies was that they were conducted prior to the latest MS GWAS and thus used fewer MS risk variants to compute their polygenic risk scores. Recent work in a Turkish cohort has suggested that population-based MS cases have a higher PRS than people with MS from multicase families; however, this comparison was not statistically significant, and not all HLA risk alleles were able to be imputed [32]. These conflicting results also reflect the heterogeneity of common genetic risk profiles for MS.…”

The Role of Parental Consanguinity and Familial Aggregation in Development of Multiple Sclerosis: A Case-control Study

“…It is possible that PC could reinforce several gene loci associated with MS (39). In a study by Everest et al, FMS cases were signi cantly more likely to experience common rare risk variation than controls and control families (41).…”

Consanguineous marriage among familial multiple sclerosis subjects: A national registry-based study

“…Despite the high prevalence of consanguinity among Emirati individuals, no significant differences in clinical and demographic characteristics were observed between those with familial and sporadic MS [ 42 ]. Previous studies have identified certain rare genetic risk variants that contribute to the heritability of MS, possibly explaining its occurrence in specific families [ 20 , 43 ], along with some hormonal contributors [ 44 ]. In contrast, additional studies have demonstrated a significant link between environmental factors and the development of MS, such as sunlight exposure, cigarette smoking, measles infection, Epstein-Barr virus (EBV) infection, and stressful events [ [45] , [46] , [47] ].…”