The nitric oxide pathway in the hippocampus is involved in the biological stress response with detrimental consequences to cells and HPA axis feedback. Hippocampal atrophy and HPA axis feedback dysfunction are associated with posttraumatic stress disorder (PTSD). This study systematically investigates two genes of the nitric oxide pathway NOS1AP and NOS1 for a potential involvement in PTSD, comorbidities and resilience. A cohort of age and gender matched Vietnam veterans including trauma-exposed cases and controls was recruited and comprehensively assessed (n=299). A total of 49 NOS1AP and 16 NOS1 polymorphisms were analysed and genotypes correlated with gold standard clinical measures to assess PTSD severity and related phenotypes (depression, anxiety, stress, resilience) based on diagnostic status. Multiple NOS1AP polymorphisms were associated across all measures, and NOS1 polymorphisms were associated with PTSD severity, stress and resilience. The GG genotype of NOS1 polymorphism rs10744891 was associated with PTSD severity (surviving multiple correction) while the combined TT-TG genotypes were associated with resilience (p=0.005; p=0.033, respectively). This study indicates that NOS1AP and NOS1 from the nitric oxide pathway are likely to play a key role in PTSD, its comorbidities and resilience. Given the essential role of NOS1AP and NOS1 in stress response they may be reliable targets for screening and intervention strategies.
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