Investigating Causal Relationships Between Major Mental Disorders and Hypertension Subtypes and Their Complications: A Mendelian Randomization Study

The association between major psychiatric disorders (major depression, bipolar disorder, schizophrenia) and hypertension has long been of clinical and research interest. Using publicly available summary data from large-scale genome-wide association studies (GWASs), we selected, quality-controlled, and clustered eligible genetic variants for the three psychiatric disorders and hypertension-related outcomes. The inverse variance weighted (IVW) method was applied as the primary analysis, with a suite of sensitivity analyses including MR-Egger regression, weighted median estimator (WME), and leave-one-out analysis performed to assess result robustness and detect potential horizontal pleiotropy. False discovery rate (FDR) correction was implemented to multiple testing. Bidirectional two-sample Mendelian randomization (MR) identified a reciprocal causal association between major depression and essential hypertension. Genetically predicted major depression was significantly associated with an increased risk of essential hypertension [IVW: odds ratio (OR) 1.247, 95% confidence interval (CI) (1.117-1.393), p < 0.001; WME: OR 1.243, 95% CI (1.127-1.371), p < 0.001]. Conversely, genetic predisposition to essential hypertension also increased the risk of major depression (IVW: OR 1.028, 95% CI (1.007-1.050), p = 0.008), which remained significant after FDR correction. We found that bipolar disorder was causally associated with essential hypertension, hypertensive heart disease, and hypertensive renal disease (p < 0.05). In contrast, no causal associations were observed between schizophrenia and any hypertension subtypes or complications (p > 0.05). All sensitivity analyses confirmed the robustness of the primary effect estimates, with no evidence of significant horizontal pleiotropy or influential outliers. In conclusion, our study, conducted under the MR framework from the perspective of genetic susceptibility, supports a bidirectional causal relationship between major depression and essential hypertension.