Background and purpose: Although observational studies have reported a positive association between depression and ischemic stroke, causality remains inconclusive. We aimed to assess the causal relationship of major depressive disorder (MDD) with ischemic stroke, especially with the small vessel stroke (SVS) subtype.
Methods: We used 72 independent single-nucleotide polymorphisms associated with MDD in a genome-wide association study (GWAS) from the Psychiatric Genetics Consortium as instrumental variables. The corresponding data for ischemic stroke and its subtypes of European ancestry were available from the MEGASTROKE consortium of 34,217 ischemic stroke cases and 406,111 controls. Primary Mendelian randomization estimates were calculated with inverse-variance weighted method, and several alternate methods and multiple sensitivity analyses were also performed.
Results: We found that genetic predisposition to higher risk of MDD was associated with higher risk of SVS, with an odds ratio of 1.33 (95% confidence interval, 1.08-1.65; p = 0.009) per log-odds increment in MDD risk, but not with large artery stroke (OR, 1.08; 95% CI 0.83-1.41; p = 0.559), cardioembolic stroke (OR, 0.98; 95% CI 0.80-1.20; p = 0.833), or all ischemic stroke (OR, 1.03; 95% CI 0.92-1.15; p = 0.633). The association of MDD with SVS was overall robust to sensitivity analyses.
Conclusions: We provided evidence for a possible causal effect of MDD on increased risk of SVS. Future researches are required to investigate whether rational intervention on depression may help to reduce societal burden of SVS.
Keywords: Ischemic stroke; Major depression; Mendelian randomization; Single-nucleotide polymorphism; Small vessel stroke.