Abstract
OBJECTIVE: A better understanding of factors associated with multiple sclerosis (MS) disease activity and disability is needed. Given the strong link between comorbid depression and MS disease activity and disability, we aimed to determine whether the depression genetic burden, as modelled using its polygenic score, is associated with MS disease activity and disability worsening. METHODS: In this cohort study, we used samples from neurologist-defined adult people with MS (PwMS) followed in clinical care or during a clinical trial from existing cohorts: Canada, the United States (US), and Sweden with extensive longitudinal phenotypes. We computed the depression polygenic score (PGS) and tested its association with annualized relapse rate and worsening disability. In the US cohort, we additionally explored the time to relapse, number of enhancing lesions, and confirmed Expanded Disability Status Scale (EDSS) worsening during the study period. RESULTS: We included 3,420 relapsing-onset PwMS of European genetic ancestry with a median follow-up of 3 to 5 years. Meta-analyses revealed for each 1-standard deviation increase in the depression PGS, the relapse rate increased (incidence rate ratio: 1.23, 95% confidence interval [CI] = 1.01-1.50). In the US cohort, higher depression PGS was associated with protocol-defined relapses (hazard ratio [HR] = 1.58, 95% CI = 1.03-2.43), and time to confirmed EDSS worsening (HR = 1.51, 95% CI = 1.03-2.22) with this effect largely direct. INTERPRETATION: Meta-analyses showed a higher depression genetic burden was associated with increased MS disease activity. In the US clinical trial cohort only, we found a significant association between higher depression PGS and time to relapse and confirmed EDSS worsening. These findings may provide insights into MS disease activity and disability worsening. ANN NEUROL 2025;98:1057-1069.