Immune-metabolic mediation of depression risk: Causal evidence from antibody and metabolite GWAS

Depression is a major contributor to global disability, yet its underlying biological mechanisms remain incompletely understood. Immune activation and metabolic alterations, particularly involving lipid metabolism, have been implicated, but their roles in depression remain unclear. We used large-scale genome-wide association study (GWAS) summary statistics to examine the relationships among antibody responses, plasma metabolites, and depression. Mendelian randomization (MR) was applied to evaluate genetically predicted associations of antibody traits and metabolites with depression risk. Generalized summary-data-based Mendelian randomization (GSMR) was used as a complementary analysis, and two-step mediation analyses were performed to assess whether selected metabolites were compatible with mediating immune-related effects on depression. Higher Epstein-Barr virus (EBV) ZEBRA antibody levels were associated with increased depression risk, whereas arachidonate-enriched metabolites tended to show inverse associations with depression and several linoleoyl-related metabolites showed positive associations. Mediation analyses suggested that 1,2-dilinoleoyl-GPC showed a positive indirect effect, whereas 1-arachidonylglycerol showed a negative indirect effect. Two glycerolipid ratios also showed indirect effects consistent with partial mediation. Complementary GSMR analyses showed directionally concordant results for the principal associations. Overall, these findings support an immunometabolic interpretation in which EBV-related immune responses and plasma metabolite remodeling may be relevant to depression vulnerability, and they prioritize candidate metabolites and pathways for future mechanistic and clinical investigation.