Causal relationships between blood lipids and depression phenotypes: A Mendelian randomization analysis

Depression is one of the most significant contributors to disability worldwide, yet its etiology is not well understood. Changes in blood lipid levels such as reduced cholesterol have long been suspected to be associated with depression and suicide. Here we performed a two-sample bi-directional MR analysis to investigate their causal relationship, based on large-scale GWAS summary statistics (N up to 188,577 and 480,359 for lipid and depression traits respectively). Five depression-related phenotypes were included, namely major depressive disorder (MDD), depressive symptoms (DS), longest duration and number of episodes of having low mood, and history of deliberate self-harm (DSH) or suicide. MR was conducted with several approaches including inverse-variance weighted, Egger regression and Generalized Summary-data-based MR (GSMR). We found that reduced low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) were causally related to higher risks of MDD (OR for 1-SD decrease in LDL-c: 1.07, 95% CI 1.05-1.10, p= 3.15E-08; OR for 1-SD decrease in TC: 1.08, 95% CI 1.04-1.12, p=2.94E-04) and more prolonged depressed/low mood. Lower LDL-c was also found to be causally linked to more severe DS. In addition, we observed that lower levels of high-density lipoprotein cholesterol (HDL-c) was casually related to increased DS, as well as heightened risks of DSH or suicide (OR=2.17, CI: 1.40-3.39). As for triglycerides (TG), we observed positive causal associations with DS, number of episodes of low mood and risks of DSH or suicide (OR=1.58, CI: 1.16-2.17). We did not detect any significant associations when depression phenotypes were treated as the exposure. Taken together, the current study suggests a causal relationship between reduced cholesterol and raised TG with risks of depression and related phenotypes. Further studies on its mechanistic basis and the clinical effects of lipid-lowering therapies may be warranted.