Transcriptome-wide comparison of MDD and bipolar disorder reveals convergent glial-immune risk and divergent synaptic timing mechanisms

Major depressive disorder (MDD) and bipolar disorder (BIP) share substantial genetic risk yet differ markedly in clinical course. To clarify shared and disorder-specific mechanisms, we performed parallel transcriptome-wide association studies (TWAS) using the largest available European-ancestry GWAS summary statistics (MDD: N ≈ 829,000; BIP: N ≈ 191,000). Genetically regulated gene expression was imputed in six GTEx v8 brain tissues with 13 curated, non-overlapping gene sets spanning synaptic plasticity, pruning, complement, senescence, oligodendrocyte function, and immune pathways. Cross-disorder comparisons included Stouffer meta-Z correlation, rank-rank hypergeometric overlap, and differential association testing. Results were anchored in normative developmental trajectories from the BrainSpan atlas.We observed moderate positive correlation of transcriptomic signals between disorders (Pearson r = 0.29) and 72.1% directional concordance among jointly significant genes. Histocompatibility complex and oligodendrocyte marker sets were enriched in both conditions, with consistent positive associations at C4A and GLYCTK. MDD showed additional enrichment for long-term potentiation and synaptic plasticity pathways, driven by stronger effects at oxidative regulators such as GPX1. Bipolar disorder displayed relatively stronger senescence signals and specific associations at mTOR-related genes (e.g., RPTOR) with opposite-direction effects at adhesion molecules (e.g., PCDHA13). Direct synapse-pruning genes were not enriched in either disorder. BrainSpan analyses revealed largely stable expression of pruning, complement, and oligodendrocyte genes from adolescence into adulthood in prefrontal cortex, indicating that risk variants likely modulate timing or cellular sensitivity rather than bulk transcript levels.These findings support a model in which a shared glial-immune platform creates inefficient synaptic refinement in both disorders, while disorder-specific modifiers produce chronic rigidity in MDD versus oscillatory pruning timing in BIP. The results highlight potential mechanism-based therapeutic nodes and provide a developmental framework for future functional studies.