ADCYAP1R1 encodes a G protein-coupled receptor (PAC1) that binds the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), recognizing both PACAP27 and PACAP38 variants 12. Ligand binding triggers conformational changes that activate cAMP-dependent signaling pathways through G protein coupling 13. The receptor regulates multiple neuroendocrine functions, including release of adrenocorticotropin, growth hormone, and catecholamines, and modulates smooth muscle relaxation in the gastrointestinal tract 13. In neurons, PAC1 signaling promotes dendritic spine density and mitochondrial content, supporting synaptic plasticity and energy homeostasis critical for cognitive function 4. Functionally, ADCYAP1R1 modulates emotional processing and stress responses 5. Genetic variants, particularly rs2267735, show significant associations with posttraumatic stress disorder (PTSD), particularly in women, with the C allele conferring increased risk 6. This variant also demonstrates gene-by-environment interactions, where CC genotype combined with high neighborhood crime or violence exposure predicts elevated major depression symptoms and fear-conditioned responses in trauma-exposed populations 78. Additionally, ADCYAP1R1 variants associate with childhood asthma, modulated by epigenetic methylation patterns and violence exposure 9. These findings identify PAC1 as a stress-system modulator relevant to neuropsychiatric and physical health outcomes.