From Pruning to Plasticity: Refining the Etiological Architecture of Major Depressive Disorder Through Causal and Polygenic Inference

Background: Major depressive disorder (MDD) is a highly heritable psychiatric condition with complex polygenic architecture. Competing hypotheses emphasize glutamatergic/synaptic plasticity deficits or neurodevelopmental synaptic pruning dysregulation, but integrated testing across large-scale genetic data remains limited. Methods: We re-analyzed the latest Psychiatric Genomics Consortium MDD GWAS (approximately 358,000 cases and 1.28 million controls, European ancestry) using gene-based and competitive gene-set testing (MAGMA), partitioned heritability (LDSC), transcriptome-wide association studies (TWAS with GTEx v8 brain models), and two-sample Mendelian randomization (MR) with cognitive reserve proxies (e.g., educational attainment). Results: MAGMA and LDSC revealed robust enrichment in synaptic pruning-related gene sets (Bonferroni-corrected p < 0.001; up to 1.30-fold LD-adjusted heritability enrichment, p < 10-91), surpassing glutamatergic/plasticity sets (moderate MAGMA enrichment, p = 0.014; no LDSC signal). TWAS showed modest glutamatergic enrichment (1.10-fold mean |Z|, p = 0.007) with heterogeneous directions, while pruning sets were null in TWAS despite strong polygenic signals. MR demonstrated causal protective effects of genetically proxied cognitive reserve on MDD risk (e.g., educational attainment OR = 0.72, 95% CI [0.66–0.79], p = 7.53 × 10-14). Conclusions: These findings prioritize developmental synaptic pruning dysregulation as the primary polygenic substrate of MDD, with downstream impairments in neuroplasticity and cognitive reserve mediating vulnerability. We propose a "pruning-mediated plasticity deficit" framework, integrating neuroimmune and circuit-level mechanisms, with implications for novel therapeutics targeting pruning pathways or plasticity enhancers.