Bridging GWAS and Function: Transcriptomic Signatures of Early- Versus Late-Diagnosed ADHD and Implications for Treatment Heterogeneity

Attention-deficit/hyperactivity disorder (ADHD) is heterogeneous in the age at which symptoms first lead to clinical diagnosis. Recent genomic analyses of a large Danish population-based cohort showed that individuals diagnosed in childhood differ from those diagnosed in adulthood in polygenic risk scores, rare-variant burden, and patterns of genetic correlation with other psychiatric traits [1]. Childhood cases exhibited stronger overlap with autism and higher rates of rare protein-truncating variants in constrained genes, whereas late-diagnosed cases showed greater genetic overlap with depression. The functional transcriptomic mechanisms underlying these differences have remained unclear.We performed a transcriptome-wide association study (TWAS) using S-PrediXcan and GTEx v8 MASHR models from six adult brain tissues (amygdala, anterior cingulate cortex, caudate, frontal cortex, hippocampus, nucleus accumbens). Analyses were based on GWAS summary statistics from the iPSYCH study for childhood ADHD (N = 14,878) and late-diagnosed ADHD (N = 6,961). Thirteen curated gene sets were examined, spanning synaptic plasticity, immune function, glial markers, and housekeeping controls.The transcriptomic profiles of the two subgroups showed substantial overall similarity (Spearman ρ = 0.77 across 13,580 genes), with near-perfect directional concordance among nominally significant associations. Despite this shared architecture, pathway analyses revealed clear divergences: late-diagnosed ADHD displayed stronger enrichment in long-term potentiation (enrichment ratio = 1.34, Mann-Whitney p = 1.42 × 10⁻⁸) and complement cascade pathways (1.22, p = 5.14 × 10⁻⁵), whereas childhood ADHD showed relatively greater signals in microglia marker and MHC genes. Eighty-two genes differed significantly in association strength between the groups after FDR correction.These findings provide a functional explanation for previously reported genetic and comorbidity differences by age at diagnosis. The enrichment patterns generate hypotheses regarding potential variation in stimulant response and tolerability, although direct treatment data were not available. This represents the first TWAS to dissect ADHD subtypes by age at first diagnosis and offers a bridge between statistical genetic associations and biologically interpretable pathways relevant to clinical heterogeneity.Keywords: ADHD subtypes, transcriptome-wide association study, long-term potentiation, complement cascade, microglia, stimulant response, precision psychiatry