Mendelian Randomization Identifies Lipidomic Signatures of Depression Risk That Are Partly Reflected in...

Major depressive disorder (MDD) is associated with altered membrane lipids, but the causal species remain uncertain. Using two-sample Mendelian randomization (MR) on lipidomic GWAS data and the latest MDD meta-analysis (~400,000 cases; 1.5 million controls), we identified 49 lipid species linked to MDD risk, notably enriched for phosphatidylcholines. Protective lipids were enriched for long-chain polyunsaturated fatty acids (20:3-20:5), whereas shorter-chain or less unsaturated species, particularly 18:2-containing lipids, increased risk. These associations were also observed in a subset of clinically assessed MDD cases. Colocalization supported shared causal variants between many lipid traits and MDD, prominently at the FADS1/2 locus and additional loci, suggesting multiple entry points into lipid metabolism that differ partly from bipolar disorder. MR-implicated lipid shifts overlapped with cortisol-induced changes in a human cell stress model and were often reversed by co-treatment with St. John's wort extract (Ze 117). Cholesteryl ester 20:3 emerged as a robust candidate marker, showing protective MR effects in two cohorts, colocalizing genetic support, normalization by Ze 117, and an inverse correlation with depressive symptom severity in a non-clinical sample. Together, these results define a depression-associated lipidomic signature centered on polyunsaturated fatty acid metabolism with biomarker and therapeutic potential.