Opposite Transcriptomic Directions at Shared Risk Loci in Late-Diagnosed ADHD and ASD

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share substantial genetic risk yet display markedly different clinical presentations. Genome-wide association studies report moderate positive genetic correlations between the disorders, but the functional directionality of shared loci at the transcriptome level—and whether age at diagnosis modifies these effects—has remained unclear. We addressed this gap with a symmetric 2×2 transcriptome-wide association study (TWAS) comparing early- and late-diagnosed subgroups of both conditions.Using S-PrediXcan models across six matched brain regions (amygdala, anterior cingulate cortex BA24, caudate, frontal cortex BA9, hippocampus, nucleus accumbens) and Stouffer meta-analysis, we generated cross-tissue Z-scores for 10,229 overlapping genes. Transcriptome-wide correlations were near zero and non-significant in three comparisons (r = −0.014 to +0.012, all p > .15). In contrast, late-diagnosed ADHD versus late-diagnosed ASD showed a modest but significant negative correlation (Pearson r = −0.0261, p = .008; Spearman ρ = −0.0307, p = .002). Direction concordance among nominally significant genes remained ~50%, while FDR-significant gene overlap was consistently enriched (OR 1.75–2.25). We identified 1,306–1,461 genes with significant opposite directional effects (ΔZ test, FDR < .05), with recurrent large-effect signals at mitochondrial (CISD2, ATP23), adhesion (NEGR1), proteostasis (GID4, UBE2D3), and synaptic-stabilization (CSPG5) loci—effects strongest in late-diagnosed comparisons and regionally enriched in the anterior cingulate cortex and nucleus accumbens.These findings support the Late-Diagnosis Anti-Correlation Hypothesis: late-diagnosed cases may represent compensatory subtypes in which shared risk loci trigger opposing transcriptional responses that initially buffer symptoms and delay clinical recognition. If replicated, this pattern could inform direction-aware polygenic scores and more personalized neurodevelopmental interventions.Keywords: TWAS, ADHD, ASD, diagnosis timing, compensatory subtypes, mitochondrial genes, NEGR1