Abstract
BACKGROUND: Previous studies have demonstrated a correlation between mental disorders and hypertension. However, the direction of this association and the specific risk factors that mediate the causal effects remain unknown. The present study aimed to investigate the causal relationship between mental disorders and hypertension, as well as identify the risk factors that mediate it. METHODS: We used univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR) to evaluate the causal relationship between depression, anxiety, or panic attacks and hypertension using the summarized statistics from eleven extensive genome-wide association studies in European populations. Furthermore, MVMR was used to evaluate seven potential mediators of this association and calculate their mediated proportions. The robustness of our findings was evaluated using sensitivity analyses. RESULTS: UVMR analysis revealed that genetically predicted higher risk of depression (OR: 1.140, 95%CI: [1.075, 1.210], p < 0.001), anxiety (OR: 2.679, 95%CI: [1.328, 5.408], p < 0.01), and panic attacks (OR: 1.054, 95%CI: [1.016, 1.092], p < 0.01) were associated with increased risk of hypertension. Higher risk of hypertension was also associated with higher risk of depression (OR: 1.101, 95%CI: [1.009, 1.202], p < 0.05). Of seven candidate mediators, two met the screening criteria and were included in the mediation MR analyses. The MVMR analysis revealed that even after adjusting for depression, there was a persistent causal relationship between type 2 diabetes and hypertension (OR: 1.010, 95%CI: [1.005, 1.015], p < 0.001). Similarly, the causal relationship between smoking and hypertension remained significant after accounting for depression (OR: 1.037, 95%CI: [1.015, 1.060], p < 0.001). Mediation analyses indicated that diabetes and smoking have mediation effects of 8.71% and 5.79% between depression and hypertension, with mediation proportions of 41.7% and 27.7%, respectively. CONCLUSION: This study provided compelling evidence supporting a bidirectional phenotypic association between depression and hypertension, while highlighting diabetes and smoking as significant mediators in the association's pathway to hypertension development.