Effects of metabolic factors in mediating the relationship between Type 2 diabetes and depression in East Asian populations: A two-step, two-sample Mendelian randomization study

Background: Observational studies suggested a close link between type 2 diabetes (T2D), metabolic factors and depression, while the causal relationships remained poorly understood. Objective: To determine the causality between T2D and depression, and to investigate the roles of metabolic factors in mediating the relationship between T2D and depression in East Asians.Methods: Using summary statistics from the largest and most up-to-date genome-wide association studies of depression (12,588 cases and 85,914 controls) and T2D (36,614 cases and 155,150 controls) among East Asians, two-step and two-sample MR analyses were performed to estimate the causal mediation effects of metabolic factors including lipid profiles, blood pressure (BP) and fasting insulin (FI) on the relationship between T2D and depression.Results: Genetically predicted T2D was significantly associated with depression (OR [95 % CI]:1.06 [1.01, 1.11], P = 0.043), but not vice versa. T2D was causally associated with lower levels of HDL-C and higher levels of LDL-C, triglycerides (TG), BP and FI. Furthermore, the causal effects of T2D on depression were significantly mediated by LDL-C (beta [95 % CI]:-0.003 [-0.005,-0.001], P = 0.007), and suggestively mediated by TG (0.001 [0.001, 0.003], P = 0.049) and FI (0.006 [0.001, 0.012], P = 0.049). Limitations: First, depression was defined by several methods, like symptom questionnaires or self-completed surveys. Second, two-sample MR approach is unable to detect the non-linear causal relationships. Third, inde-pendent data sets were not available for replication of our findings.Conclusion: T2D was causally associated with the risk of depression, and LDL-C, TG, and FI were potential causal mediators of the effect of T2D on depression. Understanding the causality among T2D, metabolic factors and depression is crucial for identifying potential targets for early intervention.