The familial risk and heritability of multiple sclerosis and its onset phenotypes: A case–control study

BACKGROUND: The two main phenotypes of multiple sclerosis (MS), primary progressive (PPMS) and relapsing Onset (ROMS), show clinical and demographic differences suggesting possible differential risk mechanisms. Understanding the heritable features of these phenotypes could provide aetiological insight. OBJECTIVES: To evaluate the magnitude of familial components in PPMS and ROMS and to estimate the heritability of disease phenotypes. METHODS: We used data from 25,186 MS patients of Nordic ancestry from the Swedish MS Registry between 1987 and 2019 with known disease phenotype (1593 PPMS and 16,718 ROMS) and 251,881 matched population-based controls and 3,364,646 relatives of cases and controls. Heritability was calculated using threshold–liability models. For familial odds ratios (ORs), logistic regression with robust sandwich estimator was utilized. RESULTS: The OR of MS diagnosis in those with a first-degree family member with ROMS was 7.00 and 8.06 in those with PPMS. The corresponding ORs for having a second-degree family member with ROMS was 2.16 and 2.18 in PPMS. The additive genetic effect in ROMS was 0.54 and 0.22 in PPMS. CONCLUSION: Risk of MS increases by several folds in those with a relative with MS. The likelihood of developing either disease phenotype appears independent of genetic predisposition.