Cerebral small vessel disease (CSVD) and its associated stroke are significant contributors to mortality and long-term disability globally. Despite this, there remains a lack of established predictors or preventive strategies for stroke mediated by CSVD, beyond the management of hypertension. In this study, we explored the potential utility of imaging-derived phenotypes (IDPs) of white matter (WM) as risk predictors for CSVD-mediated stroke and clarify the underlying causal relationships.

We performed a genetic correlation analysis to assess the relationship between WM IDPs and CSVD-mediated stroke, identifying genetically correlated pairs for follow-up Mendelian randomization (MR) studies. Subsequently, we examined the mediating role of WM IDPs in the correlation between blood pressure (BP) traits and CSVD-mediated stroke.

Our findings demonstrate a significant causal relationship between genetic predisposition to increased isotropic or free water volume fraction (ISOVF) in the anterior limb of the left internal capsule (ALLIC) and CSVD-mediated stroke (IVW: odds ratio [OR] = 1.57; 95 % CI: 1.25 to 1.96, p = 8.27 × 10^–5).

This study provides evidence for a potential causal link between WM IDPs and CSVD-mediated stroke, which may enhance the predictive capacity for CSVD-mediated stroke.