Causal relationships between cathepsins and psychiatric disorders: A Mendelian randomization study

Introduction: Observational epidemiological studies investigating the association between cathepsins and psychiatric disorders have reported inconsistent results. Objectives: The objective of this study was to evaluate the potential causal effects of cathepsins on psychiatric disorders using Mendelian randomization (MR) analysis. Methods: A two-sample MR analysis was conducted using single-nucleotide polymorphisms as instrumental variables to examine the effects of cathepsins on psychiatric disorders. The study assessed both the individual and combined impacts of various cathepsins through univariable and multivariable MR analyses. Statistical techniques included the inverse-variance weighted method, along with supplementary approaches such as MR-egger regression, to ensure a comprehensive assessment. Results: Univariable MR analysis demonstrated a significant correlation between cathepsin G and bipolar disorder, as well as between cathepsin S and depression. In addition, multivariate MR analysis further confirmed that elevated levels of cathepsin G were significantly linked to an increased risk of bipolar disorder, while elevated levels of cathepsin S were linked to a higher risk of depression – even after adjusting for the effects of other cathepsins. Reverse MR and sensitivity analyses supported the robustness of these findings. Conclusion: This study suggests that cathepsin G and S are casually associated with an increased risk of bipolar disorder and depression, respectively. However, due to the limitations of the MR approach, including pleiotropic effects, these associations should be considered with caution.