Polygenic Dissection of Synaptic Pruning and Glutamatergic Signaling: Contrasting Mechanisms in ASD and ADHD

Autism spectrum disorder (ASD) and attention-deficit/​hyperactivity disorder (ADHD) often travel together clinically, yet they present very different pictures in day-to-day life. To see where their biology overlaps and where it parts company, we re-examined the largest available genome-wide association studies for each condition. Three complementary tools—MAGMA for gene and gene-set tests, stratified LD-score regression for partitioned heritability, and S-PrediXcan for tissue-specific transcriptome-wide association—were trained on two candidate pathways: glutamatergic neurotransmission and synaptic pruning.The picture that emerged is one of partial overlap with notable biases. Genes that build and regulate glutamatergic synapses were strongly enriched in ASD (e.g., 1.45-fold heritability boost for the core set), but they left only faint traces in ADHD. Markers of synaptic pruning, in contrast, were enriched for both disorders; yet once glutamatergic genes were removed from the lists, the pruning signal stayed significant only for ADHD. Transcriptomic clues echoed that split: in ASD, predicted down-regulation of GABBR1 may worsen hyper-excitability and drive compensatory over-pruning, whereas in ADHD up-regulation of cytoskeletal and guidance genes hints at delayed synapse elimination.Taken together, the results suggest a spectrum. ASD risk seems to couple excess excitation with secondary over-pruning, leading to the under-connected social circuits seen on imaging. ADHD, by contrast, appears rooted in sluggish pruning, leaving networks in an immature, hyper-connected state. Pinpointing when and how pruning goes off-track could open a new window for intervention and illustrates the value of pathway-level dissection in comorbid neurodevelopmental disorders.