Investigating The Causal Effects of Chronic Metabolic Traits on Stroke and The Mediating Role of Depression: Evidence From Mendelian Randomization.

Chronic metabolic traits such as body mass index (BMI), obesity, and type 2 diabetes (T2D) are known risk factors for cerebrovascular diseases. Depression, often comorbid with metabolic disorders, may mediate these associations. A two-sample Mendelian randomization (MR) analysis was conducted to examine the causal effects of genetically predicted BMI, obesity, and T2D on small-vessel stroke (SVS) and major depressive disorder (MDD). The relationship between depression and SVS was further assessed, and a two-step MR mediation analysis was applied to explore whether depression mediates the associations between chronic metabolic traits and SVS risk. Higher BMI, obesity, and T2D were significantly associated with increased risk of SVS (BMI: OR = 1.25, p = 1.27 × 10-3; Obesity: OR = 1.09, p = 0.032; T2D: OR = 1.17, p = 1.14 × 10-7). All three traits also elevated risk of MDD (BMI: OR = 1.20, p = 3.31 × 10-10; Obesity: OR = 1.06, p = 0.006; T2D: OR = 1.03, p = 0.035). MDD, in turn, increased the risk of SVS (OR = 1.11, p = 0.035). Mediation analyses indicated that depression showed a potential partial mediating effect on the BMI-SVS association (indirect effect = 0.019, p = 0.046), while mediation via obesity or T2D was non-significant. These results highlight the importance of addressing comorbid depression in individuals with metabolic disorders to reduce cerebrovascular risk.