Elucidating Immune Cell Mediated Causal Pathways Linking Blood Metabolites to Major Depressive Disorder: A Mediation...

Metabolic and immune alterations have been reported in patients with major depressive disorder (MDD), yet the biological pathways linking these changes to MDD remain incompletely understood. This study aims to examine the association between blood metabolites and the risk of MDD, investigate the mediating role of immune cells, and explore their causal relationships.

We analyzed genome-wide association study (GWAS) summary statistics for 1400 circulating metabolites and 731 immune-cell traits, together with an MDD GWAS comprising 135,458 cases and 344,901 controls, all obtained from the GWAS Catalog and the Psychiatric Genomics Consortium. Causal effects of each metabolite on MDD were estimated with seven Mendelian randomization (MR) approaches: inverse variance weighted, MR-Egger, weighted median, debiased inverse variance weighted method (IVW), Bayesian weighted MR, Mendelian randomization robust adjusted profile score (MR-RAPS), and constrained maximum likelihood and model averaging. Horizontal pleiotropy was evaluated with Mendelian Randomization Pleiotropy RESidual Sum and Outlier method (MR-PRESSO), RadialMR, and the MR-Egger intercept, whereas Cochran's Q statistic and leave-one-out analyses assessed heterogeneity and sensitivity. Finally, MR-based mediation analysis quantified the extent to which immune-cell traits mediate the metabolite-MDD associations.

MR analyses provided evidence consistent with potential causal effects of 10 metabolites, including 1-(1-enyl-stearoyl)-2-linoleoyl-GPE, 2-linoleoylglycerol, kynurenine, spermidine-to-histidine ratio, 1-linoleoylglycerol, 4-vinylguaiacol sulfate, dopamine 4-sulfate, N-acetyl-aspartyl-glutamate, sphingomyelin and taurine to glutamate ratio and MDD. Mediation analyses identified three immune-cell-mediated pathways: CD8dim T cells mediated 5% of the effect of 2-linoleoylglycerol on MDD risk; CD11b expression on basophils mediated 19% of the effect of dopamine 4-sulfate on MDD risk; and CD4 expression on resting regulatory CD4 T cells mediated 14% of the effect of the spermidine-to-histidine ratio on MDD risk.

Our findings suggest that specific metabolites may affect the risk of MDD via immune-related pathways.