Common Genetic Risk Variants for PTSD Are Enriched in AMPA and NMDA Receptor Genes: Implications for Glutamatergic Therapeutic Strategies

Background: Post-traumatic stress disorder (PTSD) is associated with impaired fear extinction and synaptic loss in prefrontal–limbic circuits. Converging evidence implicates glutamatergic dysfunction in these deficits, yet the genetic architecture underlying glutamatergic involvement in PTSD remains incompletely understood. Methods: We applied MAGMA gene-based and competitive gene-set analyses to the largest PTSD GWAS to date (European ancestry, effective N = 638,463; Nievergelt et al., 2024). We tested prespecified gene sets including ionotropic glutamate receptor subunits (AMPA, NMDA, kainate), downstream plasticity mediators, metabolic enzymes (e.g., CYP2D6), and negative control sets (monoaminergic and housekeeping genes). Partitioned heritability was used to assess enrichment of PTSD common-variant risk in functional categories. Results: Genome-wide significant association was observed at GRIA1 (GluA1 AMPA subunit; Z = 5.78, p = 3.77 × 10⁻⁹). Partitioned heritability revealed strong enrichment for AMPA/kainate receptors (enrichment ratio = 1.36, p ≈ 10⁻¹³), NMDA receptor subunits (ratio = 1.25, p ≈ 10⁻⁷), and metabolic enzymes including CYP2D6 (ratio = 2.08, p ≈ 10⁻⁵). A broader glutamate/plasticity gene set (n = 130) showed modest but significant enrichment (mean Z = 1.013 vs genome-wide 0.780; p = 0.024, FDR = 0.048). Negative control sets were not enriched. Conclusion: Common genetic risk for PTSD is disproportionately localized to genes encoding AMPA and NMDA receptor subunits and related metabolic enzymes. These findings provide robust genetic support for glutamatergic mechanisms in PTSD pathophysiology and highlight ionotropic glutamate receptors as promising therapeutic targets for future investigation.