Genetic Burden of Depression Linked to Increased MS Disease Activity and Disability

A higher genetic burden for depression is significantly associated with increased disease activity and worsening disability in people with multiple sclerosis (MS), according to a study published in Annals of Neurology.¹ The findings are the first, to the authors’ knowledge, to report an association between increased cumulative depression genetic burden and MS disease activity.

While the use of genetic data helps minimize reverse causality, the study does not definitively establish causality between depression predisposition and MS outcomes. | Image credit: New Africa - stock.adobe.com.

Depression is one of the most common comorbidities in MS, and previous epidemiological studies have already established a link between the conditions.^2,3 However, these studies have struggled to rule out reverse causality, where MS disease activity or disability worsening might lead to depression, rather than the other way around, the authors explained.¹ By focusing on genetic predisposition, the researchers were able to investigate whether factors associated with depression genetics are linked to MS disease outcomes even in the absence of a depression diagnosis, providing a clearer picture of the relationship.

The study included 3420 patients with relapsing-onset MS in 4 studies from Canada, the United States, and Sweden, with a median follow-up of 3 to 5 years. The objective was to determine whether the genetic predisposition for depression, measured using a polygenic score (PGS), is linked to MS disease activity and disability worsening. The study focused on genetic factors because, unlike a clinical diagnosis of depression, they are established at birth and do not change over a person's lifespan, helping to mitigate the issue of reverse causation.

“Genetic variation can provide insights in disease mechanisms or can be used for risk stratification with respect to disease outcomes, potentially before their clinical manifestation,” the authors explained. “A polygenic score (PGS) captures a given trait's cumulative genetic burden for a trait or disease. A PGS is the number of inherited common risk or protective variants, weighted by their effect sizes and computed using summary statistics from genome-wide association studies (GWAS) of various traits and diseases.”

The meta-analysis showed that for every 1-SD increase in the depression PGS, the annualized relapse rate increased by 23% (incidence rate ratio, 1.23; 95% CI, 1.01-1.50). In an analysis of the US cohort specifically, a higher depression PGS was also significantly associated with a 58% increased risk of protocol-defined relapses (HR, 1.58; 95% CI, 1.03-2.43) and a 51% increased risk of confirmed Expanded Disability Status Scale (EDSS) worsening (HR, 1.51; 95% CI, 1.03-2.22), a standardized measure of disability level in patients with MS. The authors noted that the US cohort had data available on the precise date of relapse, and the effect on EDSS was largely direct.

“Mediation analyses indicated a substantial direct effect of depression PGS on MS relapses and disability worsening in the US cohort,” the authors wrote. “This suggests shared biological processes contribute to the depression diagnosis and MS outcomes. Targeting (or treating) depression may not reduce relapse rates, although it may have a slight benefit on disability progression.” The findings were not replicated in the Canadian cohort, however, the authors noted. “Further evaluation of mechanisms is needed and whether antidepressants would affect the outcomes or not considering these findings,” they added.

The authors noted several study limitations. More than 90% of the cohort was of European genetic ancestry, limiting the generalizability of the results. Future genetic studies that specifically include people with MS from non-European ancestries are also needed, they added. While the use of genetic data helps to minimize reverse causality, the study does not definitively establish causality between the depression PGS and MS outcomes.

“A higher depression genetic burden was associated with increased MS disease activity in a meta-analysis comprised of 4 cohorts,” the authors concluded. “In the only clinical trial cohort, we found a significant association between higher depression genetic burden and the time to relapse, confirmed EDSS worsening and enhancing lesions. Our findings, at least partially, exclude reverse causality as the sole reason for worse outcomes in those with MS and depression.”

References

1. Manouchehrinia A, Fitzgerald KC, Salter A, et al. Depression polygenicity and disease activity and disability worsening in multiple sclerosis. Ann Neurol. Published online August 7, 2025. doi:10.1002/ana.70020

2. Binzer S, McKay KA, Brenner P, Hillert J, Manouchehrinia A. Disability worsening among persons with multiple sclerosis and depression: a Swedish cohort study. Neurology. 2019;93(24):e2216-e2223. doi:10.1212/WNL.0000000000008617

3. McKay KA, Tremlett H, Fisk JD, et al. Psychiatric comorbidity is associated with disability progression in multiple sclerosis. Neurology. 2018;90(15):e1316-e1323. doi:10.1212/WNL.0000000000005302