Developmental Synaptic Sparsification and Adult Plasticity Failure Jointly Underlie the Polygenic Architecture of Major Depressive Disorder

Major depressive disorder (MDD) is highly polygenic, yet the relative contributions of synaptic pruning and plasticity pathways remain unresolved. Prior genetic studies have been limited by investigator-defined gene sets and reliance on adult brain expression data, leaving the developmental timing of risk mechanisms unclear.We re-analyzed the European-ancestry subset of the 2025 Psychiatric Genomics Consortium MDD GWAS (357,636 cases, 1,281,936 controls) using 13 standardized, non-overlapping public gene sets (GOBP, KEGG, Reactome, cell-type markers, and HGNC HLA). Analyses included MAGMA competitive gene-set testing, stratified LDSC partitioned heritability, S-PrediXcan transcriptome-wide association in six GTEx v8 brain regions, two-sample Mendelian randomization with cognitive-reserve proxies, and developmental RNA-seq trajectories from the BrainSpan Atlas (prefrontal cortex and hippocampus across six lifespan periods).MAGMA and TWAS highlighted regulation of synaptic plasticity and long-term potentiation (strongest signals in GOBP Regulation of Synaptic Plasticity and KEGG Long-Term Potentiation), while LDSC showed peak heritability enrichment in the GOBP Synapse Pruning set (1.588-fold). Adult oligodendrocyte markers were enriched in TWAS, and the HGNC Histocompatibility Complex was markedly depleted in LDSC (0.315-fold). BrainSpan data revealed that both pruning and plasticity gene sets upregulated sharply from prenatal to infant stages (p < 3 × 10⁻⁶), with oligodendrocyte markers showing the steepest postnatal rise. Genetically predicted educational attainment causally reduced MDD risk (OR = 0.72).These findings support a data-driven two-stage model of MDD genetic risk—early developmental synaptic sparsification followed by adult plasticity failure—with oligodendrocyte support as an additional buffer. The temporal framework clarifies intervention timing and identifies oligodendrocyte pathways as promising therapeutic targets.