Causal Association between Kynurenine and Depression: An Investigation using Mendelian Randomization

Background: With advances in medical research, a growing association has been observed between kynurenine and depression. However, the causal relationship between kynurenine and depression remains unclear. Therefore, we utilized Mendelian randomization (MR) methods to investigate the causal link between kynurenine and depression. Methods: : We utilized extensive data from large-scale genome-wide association studies to identify single nucleotide polymorphisms that act as instrumental variables for kynurenineand depression in European ancestry populations, ensuring compliance with MR assumptions. We employed five MR algorithms, namely, weighted median, MR Egger, inverse variance weighted (IVW), simple mode, and weighted mode, with IVW as the primary analysis method. Sensitivity tests were conducted using Cochran's Q test, MR‒Egger intercept test, MR Pleiotropy Residual Sum and Outlier, and Leave-one-out analysis. Results: : The IVW analysis revealed that each standard deviation increase in kynurenine corresponded to a 1.4-fold increase in the risk of depression (OR=1.351, 95% CI=1.110~1.645, P=0.003). The direction of the effect size (positive or negative) was consistent with the findings from the other four algorithms. Sensitivity tests indicated no heterogeneity or horizontal pleiotropy among the instrumental variables. Conclusion: Elevated levels of kynurenine have a causal relationship with an increased risk of developing depression.