Abstract
BACKGROUND AND PURPOSE: Lacunar stroke is a complex, multifactorial disease with significant genetic underpinnings. However, the mechanisms through which genetic predispositions and risk factors contribute to its pathogenesis remain poorly understood. We investigated whether genetically predicted white matter (WM) microstructure mediates causal relationships between risk factors and lacunar stroke. METHODS: Data from genome-wide association studies were used to perform two-sample Mendelian randomisation (MR) analyses. Genetic variants associated with risk factors (n=34 461-898 130), lacunar stroke (n=232 596) and eight MRI-derived WM microstructural metrics across 48 tracts (n=20 859-20 860) were analysed. Univariable MR assessed causal effects of risk factors on lacunar stroke. Two-step MR analysis evaluated mediation roles of WM microstructure, whereas multivariable MR accounted for confounders. RESULTS: Hypertension was identified as the strongest risk factor for lacunar stroke (OR=1.38; 95% CI: 1.28 to 1.50, p=4.43×10(-15)). Only hypertension showed a significant causal association with genetically predicted WM microstructure. Elevated mean diffusivity (MD), isotropic volume fraction (ISOVF) and the tertiary eigenvalue in the anterior limb of the internal capsule (ALIC) were independently linked to increased lacunar stroke risk, beyond the influence of WM hyperintensities, dilated perivascular spaces and brain volume. Mediation analysis suggested that hypertension-induced lacunar stroke was partially mediated through bilateral MD and left ISOVF in the ALIC, with mediation proportions of 23.70%-33.44%. CONCLUSIONS: Hypertension may contribute to lacunar stroke pathogenesis in part through WM microstructure alterations, particularly in the ALIC. MD and ISOVF in the ALIC may serve as structural brain reserves and early biomarkers of hypertension-induced pathophysiology associated with lacunar stroke.