Interactive Effect of Plasma Lipidome on Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

Lipid metabolism disruptions are implicated in nervous and mental disorders; plasma lipidomics show promise as diagnostic and therapeutic targets. However, clarification of causal relationships between plasma lipids and neuropsychiatric disorders (NPDs) remains unclear. We employed bidirectional Mendelian randomization (MR) to examine causal links between 179 plasma lipids and 17 NPDs. Significant associations in the forward MR were further investigated using linkage disequilibrium score regression (LDSC), Bayesian colocalization (COLOC) analysis, and mediation analysis. Forward MR revealed sterol ester (27:1/16:1) and diacylglycerol (16:0_18:2) elevations may increase anorexia nervosa (AN) risk, while sphingomyelin (d36:2) elevation potentially lowers it. LDSC analysis showed no substantial genetic link between the three lipids and AN, while low posterior probability of hypothesis 4 from COLOC test disputed the presence of shared variants. Besides, AN risk elevated by sterol ester's (27:1/16:1) was suggested to mediate through C-X-C chemokine 10 downregulation. In the reverse MR, we uncovered varied causal ties: ADHD increased sterol ester (27:1/20:3), phosphatidylcholines (18:0_20:3, 18:1_20:3); Alzheimer's disease lowered phosphatidylcholine (O - 18:1_20:3); Ischemic stroke tied to less phosphatidylcholine (16:0_0:0); Obsessive-compulsive disorder exhibited a dual effect, upregulating phosphatidylcholine (16:1_18:0) and downregulating sterol ester (27:1/22:6); Parkinson's disease linked to less diacylglycerol (18:1_18:3); Schizophrenia tied to more triacylglycerols (48:0,51:1); Migraine reduced sterol ester (27:1/20:2). These insights reveal causal dynamics between plasma lipids and neuropsychiatric conditions. Our findings extend the causal landscape linking the plasma lipidome to NPDs, offering insights for the discovery of novel biomarkers and therapeutic targets in these diseases.