Genetic Factors Influencing Cerebral Small Vessel Disease and Their Link to Recovery Outcomes Following Ischemic Stroke: A Two-Sample Mendelian Randomization Study

Objective: The association between cerebral small vessel disease (CSVD) and postischemic stroke outcomes has been reported in observational studies. This study is aimed at clarifying the causal relationship between genetic predispositions to CSVD phenotypes and functional recovery after ischemic stroke using Mendelian randomization (MR).

Methods: We employed instrumental variables derived from genome-wide association studies (GWAS) of individuals of European ancestry to represent magnetic resonance imaging (MRI)-detected CSVD phenotypes, including white matter hyperintensities, cerebral microbleeds, and perivascular spaces. Data on functional outcomes after ischemic stroke were obtained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network. The primary analysis, conducted as a two-sample MR study, utilized the inverse-variance weighted approach, which was further supplemented by additional MR techniques in sensitivity analyses to validate the robustness of our findings. The Steiger directionality test was applied to evaluate the direction of the causal relationship.

Results: In the primary analysis, no significant causal associations were found between genetic markers for CSVD phenotypes and poor functional outcomes (modified Rankin Scale ≥ 3) following ischemic stroke. The odds ratios (95% confidence intervals) for the different phenotypes were as follows: 0.90 (0.49–1.64) for white matter hyperintensity volume, 1.12 (0.85–1.49) for cerebral microbleeds, 3.42 (0.79–14.85) for white matter perivascular spaces, 0.02 (0.01–6.08) for basal ganglia perivascular spaces, and 1.02 (0.01–249.21) for hippocampal perivascular spaces. Sensitivity analyses supported the reliability of these results, showing no evidence of statistical heterogeneity or directional pleiotropy. Furthermore, the Steiger directionality test confirmed the accuracy of the inferred causal directions between CSVD phenotypes and functional outcomes.

Conclusion: This MR study does not support a causal effect of genetic liability to CSVD phenotypes on functional outcomes after ischemic stroke. These findings suggest that current genetic evidence does not support a direct cause effect of CSVD phenotypes on recovery after ischemic stroke.