"Build versus refine": Transcriptomic mapping of ADHD aligns selectively with late-diagnosed autism at LRRK2- and pruning-mediated pathways

Zhang et al. (2025) demonstrated that age at autism diagnosis is not merely a matter of detection but reflects two modestly correlated polygenic factors tied to distinct developmental trajectories. Our prior transcriptome-wide association study (TWAS) translated these genetic differences into functional biology, showing that early-diagnosed autism is characterised by bioenergetic and cytoskeletal deficits during initial synapse formation (“failure to build”), whereas late-diagnosed autism is driven by astrocyte dysfunction, complement-mediated pruning, and LRRK2 dysregulation during adolescent circuit refinement (“failure to refine”). What remained unclear was where ADHD fits within this framework. Here we report a parallel TWAS on the latest ADHD GWAS summary statistics (38,691 cases, 186,843 controls; Demontis et al., 2023), using the identical S-PrediXcan pipeline, GTEx v8 MASHR models across the same six brain regions, and the same thirteen curated gene sets. We then performed direct head-to-head comparisons with the two autism strata on 11,552 overlapping genes. ADHD produced a characteristically diffuse polygenic signal, with strongest enrichment in long-term potentiation machinery, monoaminergic (especially norepinephrine synthesis and serotonin receptor) sub-pathways, and cytoskeletal tubulins; LRRK2 emerged as a top hit (rank 9, Stouffer Z = −6.692). Genome-wide and pathway-level convergence was more than threefold stronger with late-diagnosed autism (Pearson r = 0.310 on Stouffer Z-scores, 82% direction concordance, 5.56× enrichment of Bonferroni-significant genes) than with early-diagnosed autism (r = 0.094, 59% concordance). Late-diagnosed autism and ADHD jointly showed elevated limbic-enriched astrocyte, complement, and pruning signals, while early-diagnosed autism remained dominated by mitochondrial and ribosomal “build” pathways. These findings support a three-tier developmental model: early autism reflects foundational synapse-construction failure, whereas late autism and ADHD converge on adolescent refinement failure, with ADHD adding distinctive LTP and monoaminergic amplification. The framework explains why ADHD comorbidity is 3–4 times higher in late- versus early-diagnosed autism, accounts for the shifting sex ratio, and identifies precise therapeutic windows—LRRK2 kinase inhibitors and glial modulators for the late-ASD/ADHD cluster, mitochondrial support reserved for early autism. By bridging polygenic risk to transcriptomic mechanism and developmental timing, this work advances biologically stratified approaches to both conditions. Keywords: ADHD, autism heterogeneity, transcriptome-wide association study, synaptic pruning, LRRK2, developmental timing, circuit refinement