Genetic interactions between bioactive ingredients in traditional Chinese medicine and major depressive disorder,...

This study explored the genetic interactions between Traditional Chinese Medicine (TCM) bioactive ingredients and major psychiatric disorders, namely major depressive disorder (MDD), bipolar disorder (BIP), and schizophrenia (SCZ).

Predicting TCM targets using network pharmacology. Genome-wide association study (GWAS) summary statistics were analyzed using Multi-marker Analysis of Genomic Annotation (MAGMA) for gene-set association, while local heritability mapping was performed using partitioned Heritability Estimation from Summary Statistics (ρ-HESS). Tissue and cell-type enrichment was assessed using SNP set enrichment analysis (SNPsea), and functional characterization was conducted through Gene Ontology (GO) pathway enrichment with gprofiler2. Ingredient-target interactions were validated using molecular docking and molecular dynamics (MD) simulations.

In total, 273 TCM ingredient-specific gene sets were identified to be significantly associated with BIP, MDD, or SCZ (BIP:213; MDD:29; SCZ:42, p < 0.05). 10 TCM ingredients overlapped across disorders. Across 1703 Linkage Disequilibrium (LD)-independent regions, ρ-HESS detected significant non-zero local heritability in 33 (BIP), 4 (MDD), and 435 (SCZ) regions. SNPsea identified significant enrichments for BIP (n:18) and SCZ (n:22) in central nervous system tissues and immune-related cell types. GO analysis yielded 1121 significant pathways at false discovery rate (FDR)≤ 0.05 (MDD:126; BIP:802; SCZ:192), converging on inflammation, neurotransmitter regulation, and cytokine-mediated signaling. Docking of prioritized ligand-target pairs showed favorable affinities (mean binding energy -7.36 kcal/mol) with consistent poses, and molecular dynamics simulations confirmed stable complexes with plateaued RMSD and persistent key interactions.

These results demonstrate that TCM ingredients exhibit multi-target genetic associations with psychiatric disorders, mediated through brain-peripheral tissue interactions and immune-neuroinflammatory pathways. The findings provide genetic evidence supporting the potential of TCM as a polypharmacological source for novel multi-target interventions, offering insights into personalized treatment strategies for MDD, BIP, and SCZ.