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

Background The etiology of depression remains poorly understood. Changes in blood lipid levels were reported to be associated with depression and suicide, however study findings were mixed. Methods We performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between blood lipids and depression phenotypes, based on large-scale GWAS summary statistics ( N =188,577/480,359 for lipid/depression traits respectively). Five depression-related phenotypes were included, namely major depressive disorder (MDD; from PGC), depressive symptoms (DS; from SSGAC), longest duration and number of episodes of low mood, and history of deliberate self-harm (DSH)/suicide (from UK Biobank). MR was conducted with inverse-variance weighted (MR-IVW), Egger and Generalized Summary-data-based MR(GSMR) methods. Results There was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW beta for one-SD increase in TG=0.0346, 95% CI=0.0114-0.0578), supported by MR-IVW and GSMR and multiple r 2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR= 2.514, CI: 1.579-4.003). There was moderate evidence for positive associations of TG with MDD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MDD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures. Conclusions This study provides evidence to a causal relationship between TG, and to a lesser extent, altered cholesterol levels with depression phenotypes. Further studies on its mechanistic basis and the effects of lipid-lowering therapies are warranted.