Investigating the causal role of circulating metabolites in major depressive disorder

Background Metabolic dysregulation has been implicated in major depressive disorder (MDD). Aims We aimed to explore the potential role of plasma metabolites in MDD. Methods We conducted Mendelian randomisation (MR) analysis to evaluate the causal effects of 871 circulating metabolites on MDD, using the Genome‐Wide Association Studies datasets of MDD (N=1 035 760) and metabolites (N=8299). Bayesian colocalisation and druggability analyses were employed to identify genetic variants contributing to both MDD and levels of metabolites in plasma and to pinpoint metabolites with therapeutic potential, respectively. Results MR analysis identified 11 metabolites associated with MDD (false discovery rate<0.05). Eight metabolites, including arachidonate (20:4n6) (odds ratio (OR): 0.97), 1‐arachidonoyl‐GPC (20:4n6) (OR: 0.98), 1‐(1‐enyl‐palmitoyl)−2‐palmitoleoyl‐GPC (P‐16:0/16:1) (OR: 0.97), succinoyltaurine (OR: 0.98), 3‐methoxycatechol sulphate (1) (OR: 0.98) and 11β‐hydroxyandrosterone glucuronide (OR: 0.97), showed protective effects against MDD. Three metabolites were associated with increased risk, namely, butyrylglycine (OR: 1.03), 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoate (OR: 1.02) and 1‐(1‐enyl‐stearoyl)−2‐oleoyl‐GPE (p‐18:0/18:1) (OR: 1.02). Colocalisation analysis supported shared genetic signals between five lipid metabolites and MDD, particularly at loci harbouring FADS and ATP9A . Notably, a majority of metabolites associated with MDD are being explored as therapeutic targets for various psychiatric disorders. Conclusions Genetically predicted levels of certain circulating metabolites make a causal contribution to MDD. Further investigation of their roles may provide novel pathophysiological insights and give clues for targeted therapies.