Influence of two functional polymorphisms in NOS1 on baseline cortisol and working memory in healthy subjects

Nitric Oxide. 2019 Jul 1;88:45-49. doi: 10.1016/j.niox.2019.04.003. Epub 2019 Apr 16.


Introduction: The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior.

Methods: To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III).

Results: Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065).

Conclusion: For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior.

Keywords: Cortisol; Impulsivity; NOS1; Polymorphism; Schizophrenia; Working memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Healthy Volunteers
  • Humans
  • Hydrocortisone / metabolism*
  • Impulsive Behavior / physiology*
  • Male
  • Memory, Short-Term / physiology*
  • Nitric Oxide Synthase Type I / genetics*
  • Polymorphism, Single Nucleotide*
  • Reaction Time / genetics
  • Saliva / metabolism


  • NOS1 protein, human
  • Nitric Oxide Synthase Type I
  • Hydrocortisone