Targeted Glutamatergic Pathways Show Significant Enrichment in Attention-Deficit/Hyperactivity Disorder GWAS Signals

Background. Glutamatergic signaling abnormalities are increasingly linked to attention-deficit/hyperactivity disorder (ADHD); however, the extent to which glutamate-related genes shape disorder susceptibility is still unclear.Methods. Summary statistics from the most recent genome-wide association study of ADHD (38,691 cases, 186,843 controls) were re-examined with an annotation χ² framework. Twenty-three “glutamatergic regimen targets” were collated and divided into functional clusters: N-methyl-D-aspartate (NMDA) receptors, AMPA/kainate receptors, glutamate transporters, metabolic enzymes, and plasticity-related signaling molecules. Single-nucleotide polymorphisms (SNPs) within each gene ±10 kb were contrasted with all other SNPs for mean χ² values. Enrichment was evaluated with Welch’s t tests, Mann-Whitney U tests, and block jack-knife standard errors.Results. SNPs mapping to NMDA receptor genes carried a 1.25-fold excess of ADHD association signal (Mann-Whitney P = 1.3 × 10⁻⁴). Plasticity-signaling genes showed even stronger enrichment (1.41-fold; P = 4.4 × 10⁻¹⁰). When all 23 targets were pooled, a modest but significant elevation remained (1.09-fold; Welch’s t = 4.19 × 10⁻⁸). Enrichment was not detected for AMPA/kainate receptors, transporters, or metabolic genes.Conclusions. Genetic risk for ADHD is disproportionately concentrated in NMDA receptor loci and downstream plasticity genes, lending weight to models that position glutamatergic dysfunction—particularly via NMDA-dependent pathways—at the core of the disorder. These results reinforce ongoing efforts to develop glutamate-modulating therapies, including NMDA-focused agents, for individuals whose symptoms persist despite conventional treatment.