Association Between Major Depressive Disorder and the Development of Cerebral Small Vessel Disease: A Mendelian Randomization Study

BackgroundAlthough observational studies indicate a complex, bidirectional association between major depressive disorder (MDD) and cerebral small vessel disease (CSVD), the results are frequently inconsistent. This study investigated the potential correlation of MDD with both CSVD clinical outcomes and imaging markers, utilizing a bidirectional Mendelian randomization (MR) study design. MethodsInstrumental variables for both MDD and CSVD were extracted from the latest or most extensive genome-wide association study (GWAS) data available for each phenotype. Clinical outcomes and imaging markers of CSVD were defined using several parameters. The inverse variance weighting (IVW) method with additional sensitivity and heterogeneity analyses was used. Furthermore, a separate GWAS for depression was used to validate our significant findings. ResultsIn the forward MR analyses, the genetically predicted risk of MDD was positively associated with two CSVD phenotypes showing microscopic white matter (WM) damage: mean diffusivity (IVW OR = 2.191, 95 % CI 1.226 to 3.917, p = 0.008) and WM-enlarged perivascular space (OR = 1.053 95 % CI 1.006 to 1.101, p = 0.026). The use of an independent database for depression yielded no significant risk of depression associated with these two CSVD traits. Furthermore, reverse MR analyses showed no evidence of reverse causality between MDD and an altered CSVD risk. ConclusionsThis study utilizing MR imaging findings supports a substantial causal association between MDD and CSVD-related indicators of impaired WM microstructure. It is necessary to exercise caution when extending these results to individuals with depression.