From Maturational Delay to Insufficient Pruning: Genetic Insights into ADHD Neurobiology

Attention-deficit/hyperactivity disorder (ADHD) is characterized by delayed cortical maturation and persistent hyperconnectivity, features often attributed to insufficient synaptic pruning during adolescence. Despite these neurodevelopmental observations, the polygenic architecture underlying pruning dysregulation has remained unclear. Here, we re-analyzed the largest ADHD genome-wide association study (GWAS) meta-analysis to date (38,691 cases, 186,843 controls) using complementary approaches: competitive gene- and gene-set testing (MAGMA), stratified LD score regression-based partitioned heritability, and brain tissue-specific transcriptome-wide association studies (S-PrediXcan).Six hypothesis-driven gene sets were examined: two glutamatergic signaling panels (23 and 130 genes), two synaptic pruning panels (38 and 262 genes spanning complement, microglial, guidance cue, cytoskeletal, and activity-dependent mechanisms), and two negative controls (monoaminergic and housekeeping genes). The expanded pruning set consistently showed significant enrichment across methods—competitive p = 8.37 × 10⁻⁴ (Bonferroni-corrected p = 0.005) in MAGMA, highly significant χ² excess in partitioned heritability (Mann–Whitney p ≈ 10⁻¹⁵–¹⁹), and multiple FDR-significant gene-level associations in TWAS—while glutamatergic sets and controls were null.These findings provide the first robust polygenic evidence linking ADHD liability to broad synaptic pruning dysregulation, offering a molecular basis for delayed maturation and hyperconnected network states. By contrast, canonical glutamatergic pathways do not appear to harbor disproportionate common-variant risk. The results reframe ADHD as a disorder of protracted circuit refinement and highlight potential therapeutic targets in pruning-related machinery, with implications for staged interventions that promote appropriate synaptic elimination early and synaptogenesis later in the lifespan.