From Pruned Circuits to Manic Instability: Genetic Evidence for Independent Pruning Dominance and Risk-Amplifying Cognitive Reserve in Bipolar Disorder

Background: Bipolar disorder (BD) exhibits high heritability and substantial genetic overlap with schizophrenia and major depressive disorder (MDD), yet its core pathophysiological pathways remain debated. While glutamatergic dysregulation and synaptic plasticity have been emphasized, emerging evidence from schizophrenia highlights excessive synaptic pruning. We conducted a multi-method genetic analysis to competitively test pruning versus glutamatergic/plasticity hypotheses in the latest European-ancestry BD GWAS, with parallel replication in MDD for cross-disorder comparison. Methods: Using summary statistics from a large BD GWAS (effective N ≈ 137,097) and a trans-ancestry MDD GWAS (European subsample effective N ≈ 829,250), we applied: (1) MAGMA for gene-based and competitive gene-set testing with custom pruning (shortened/expanded/specific) and glutamatergic sets (original/expanded) plus controls; (2) stratified LD score regression for partitioned heritability enrichment; (3) S-PrediXcan transcriptome-wide association in six brain tissues; and (4) two-sample Mendelian randomization with neuroplasticity proxies (e.g., educational attainment). Overlap removal enabled independence assessment; directional TWAS and MR provided functional/causal insights. Results: In BD, pruning pathways dominated across methods: expanded/specific pruning sets were Bonferroni-significant in MAGMA (p = 1.14 × 10⁻⁴/7.00 × 10⁻⁴) and showed strong LDSC enrichment (p = 4.16 × 10⁻³⁸/3.77 × 10⁻¹²), persisting independently of glutamatergic overlap. TWAS revealed activation-skewed pruning (higher predicted expression in microglial/autophagy activators) with modest glutamatergic signals. MR indicated genetically proxied higher educational attainment causally increases BD risk (IVW OR = 1.403, p = 6.69 × 10⁻⁵). In MDD, pruning was robust in heritability (LDSC p < 10⁻⁹⁰) but mediated/non-enriched in expression (TWAS p > 0.7), with glutamatergic TWAS signals (p = 0.007); education was protective (OR ≈ 0.72). Conclusion: Synaptic pruning emerges as the primary, independent pathway in BD—activation-skewed and amplified by cognitive reserve into episodic instability—distinguishing it from MDD's mediated pruning deficits with protective reserve. These findings reframe BD toward neuroimmune-pruning models, with implications for targeted therapeutics and cross-disorder nosology.