Depression Polygenicity and Disease Activity and Disability Worsening in Multiple Sclerosis

Area of Science:

• Neuroimmunology
• Genetics
• Psychiatry

Background:

• Multiple sclerosis (MS) is a chronic neurological disease with significant impact on patient disability.
• Comorbid depression is strongly associated with increased MS disease activity and progression.
• Understanding the genetic underpinnings of depression's influence on MS is crucial for better management.

Purpose of the Study:

• To investigate the association between the genetic burden of depression, quantified by a polygenic score (PGS), and MS disease activity and disability worsening.
• To determine if genetic predisposition to depression predicts relapse rates and disability progression in people with MS (PwMS).

Main Methods:

• A cohort study including 3,420 relapsing-onset PwMS of European genetic ancestry from Canada, the US, and Sweden.
• Calculation of depression polygenic scores (PGS) for all participants.
• Association testing of depression PGS with annualized relapse rate, time to relapse, number of enhancing lesions, and Expanded Disability Status Scale (EDSS) worsening.

Main Results:

• Meta-analyses revealed a 1-standard deviation increase in depression PGS was associated with a 23% increase in relapse rate (IRR: 1.23, 95% CI: 1.01-1.50).
• In the US cohort, higher depression PGS correlated with protocol-defined relapses (HR: 1.58, 95% CI: 1.03-2.43) and confirmed EDSS worsening (HR: 1.51, 95% CI: 1.03-2.22).
• The observed effects were largely direct, indicating a potential biological link.

Conclusions:

• A higher genetic predisposition to depression is associated with increased MS disease activity.
• The findings suggest that genetic factors contributing to depression may directly influence MS progression and disability.
• These insights could inform future research into the interplay between genetic risk factors for depression and MS pathogenesis.