Using ordinal regression analysis, Asn-allele of NPSR1 polymorphism was nominally significantly associated with a lower risk of anxiety (OR = 0.57, CI: 0.33-0.97, p = .038) after adjusting for other covariates.
Fronto-limbic connectivity varied between NPSR1 genotypes in the developing brain suggesting a risk-increasing effect of the NPSR1T allele for anxiety-related traits via impaired top-down control of limbic structures emerging during adolescence.
Amongst neuropeptide S receptor gene functional sequence variants, the T-allele [rs324981" genes_norm="387129">asparagine(107)isoleucine, NPSR1rs324981] has been identified as a risk factor for increased anxiety/overinterpretation of bodily symptoms.
These compounds are highlighted in this study as never being used as NPSR antagonists before which provides a model for the discovery of new bioactive inhibitors that may hold potential for drug development towards anxiety, food, and addiction disorders.
In humans, associations between NPSR1 variants and anxiety and panic disorder, as well as amygdala responsiveness to fear- relevant faces and prefrontal cortex activity in a fear conditioning paradigm have been reported.
Genes related to peptide and hormone signaling have been suggested for anxiety-related phenotypes, e.g., the NPSR1 gene, which has been associated predominantly with panic disorder in women, and shown to interact with environmental factors and to influence psychometric, neurophysiological, and neuroimaging correlates of anxiety.
The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers.
Thus, a gene-environment interaction (G × E) study of the neuropeptide S receptor gene (NPSR) A/T polymorphism (rs324981) and life events was conducted with respect to anxiety sensitivity (AS) as an intermediate phenotype of anxiety disorders.
In the general population, the NPSR1 A/T polymorphism together with environmental factors is associated with anxious, depressive and activity-related traits, increased prevalence of affective/anxiety disorders and a higher likelihood of suicidal behaviour.
The current results are in line with earlier imaging genetic studies and suggest a potential protective function of the NPSR1rs324981 A/A genotype against pathologically enhanced anxiety that might be explained by stronger reflective prefrontal regulation over the subcortical fear response.
In summary, the more active NPSR1 T allele may confer enhanced response inhibition and increased error monitoring and might drive particularly error monitoring as a neurophysiological endophenotype of anxiety as reflected by increased anxiety sensitivity.
NPSR1 is expressed in the brain, where it modulates anxiety and responses to stress, but also in other tissues and cell types including lymphocytes, the lungs, and the intestine, where it appears to be up-regulated in inflammation.