Genetic Liability to Depression and Cerebral Small Vessel Disease: A Mendelian Randomization Study

To investigate the association of genetic liability to depression with cerebral small vessel disease (cSVD). Genetic instruments for liability to depression were obtained from a meta-analysis of genome-wide association studies of depression (371,184 cases and 978,703 controls). Mendelian randomization (MR) was used to examine the associations of genetic liability to depression with cSVD clinical outcomes (small vessel stroke [SVS], deep intracerebral hemorrhage [ICH]) and radiographic measures (white matter hyperintensity [WMH] volume, cerebral microbleeds [CMBs], and burden of perivascular spaces [PVS]). The primary analysis was performed using the random-effects inverse-variance weighted method. Sensitivity analyses were conducted to examine the robustness of results to violations of assumptions of MR assumptions. Genetic liability to depression was associated with a higher risk of SVS (odds ratio [OR], 1.36; 95 % confidence interval [CI], 1.14-1.62; P = 5.4 × 10-4) and deep ICH (OR, 1.82; 95 % CI, 1.14-2.89; P = 0.012). Consistent with this finding, genetic liability to depression was associated with higher WMH volume (β, 0.09; 95 % CI, 0.02-0.16; P = 0.017), but not with CMBs or PVS (P > 0.05). This study supports a potential causal effect of genetic liability to depression on cSVD. Further investigation is warranted to explore mechanisms and therapeutic implications.