Multi-Method Polygenic Investigation Implicates Dysregulated Synaptic Pruning in the Etiology of Obsessive-Compulsive Disorder

Background. Obsessive–compulsive disorder (OCD) is highly heritable, yet the biological routes through which common variants confer risk have not been fully mapped. Glutamatergic dysregulation and faulty synaptic pruning both feature prominently in mechanistic models, but direct, large-scale genetic evaluations of these pathways are scarce.Methods. We analysed summary statistics from a recent genome-wide association meta-analysis of OCD (effective sample = 68 099). Four predefined gene sets were tested: glutamatergic signalling, synaptic pruning in shortened and expanded forms, and two negative-control sets (monoamine and housekeeping genes). Three complementary tools were applied: MAGMA for competitive gene-set enrichment, stratified LD-score regression for partitioned heritability, and S-PrediXcan for transcriptome-wide association signals across six GTEx brain tissues.Results. MAGMA detected no individual genes surpassing the genome-wide threshold. In contrast, LD-score regression showed pronounced and Bonferroni-corrected heritability enrichment for pruning-related sets (shortened set: 1.32-fold, p = 1.45 × 10⁻¹⁰³; expanded set: 1.05-fold, p = 1.13 × 10⁻¹³; pruning genes with glutamatergic overlap removed: 1.06-fold, p = 7.51 × 10⁻¹⁴). Glutamatergic sets were not enriched (all p > 0.84). S-PrediXcan produced modest but significant |Z|-score inflation in the pruning-shortened (1.19-fold, p = 0.044) and glutamatergic (1.06-fold, p = 0.032) collections. Directional TWAS signals pointed to complement and microglial drivers: C4A and the microglial marker TMEM119 both showed positive Z-scores. The negative-control sets were enriched in heritability analyses but not in TWAS, suggesting residual confounding rather than true biological relevance.Conclusions. Across convergent polygenic methods, synaptic pruning genes—independent of glutamatergic overlap—emerge as the principal enrichment signal in OCD. The results fit a model in which excessive microglia- and complement-mediated pruning disrupts cortico-striato-thalamo-cortical circuit maturation, setting the stage for compulsive behaviour. This work illustrates how integrated genomic approaches can refine mechanistic hypotheses and may inform early neurodevelopmental interventions for OCD.