Uncovering associations between mental illness diagnosis, nitric oxide synthase gene variation, and peripheral nitric oxide concentration

Nitric oxide (NO) signalling has been implicated in the pathogenesis of several mental illnesses; however, its specific contribution remains unclear. We investigated whether peripheral NO concentration is associated with specific diagnoses, and whether there is a correlation with genetic variation in NO synthase (NOS) genes. We included 185 participants in the study; 52 healthy controls, 43 major depressive disorder (MDD) patients, 41 bipolar disorder (BPD) patients, and 49 schizophrenia (SCZ) patients. Clinical, genetic, and biochemical data were collected at admission to a psychiatric hospital and at discharge. Serum was used to quantify concentration of the stable NO metabolites nitrite and nitrate. Individuals were genotyped for the NOS1 exon 1f variable number of tandem repeats 1 (VNTR1) polymorphism, and single nucleotide polymorphisms (SNPs) in the NOS1, NOS1AP and NOS3 genes. At admission, SCZ patients were found to have significantly higher peripheral NO metabolite (NO_x-) concentrations compared to healthy controls, MDD and BPD patients. NOS1 exon 1f VNTR1 short allele carriers were found to have significantly increased NO_x- concentration. Moreover, this result was still significant in patients even at discharge. The data also revealed that patients who did not remit in their depressive symptoms had significantly increased NO_x- concentration compared to remitters at discharge, supported by the finding of a significant positive correlation between depression symptom severity and NO_x- concentration. Taken together, it is possible that elevated peripheral NO_x- concentration is associated with increased severity of psychopathology, potentially due to NOS1 exon1f VNTR1 genotype. Our results further implicate NO signalling in mental illness pathogenesis, supporting its possible use as a peripheral biomarker, and imply that NOS genotype may play a significant role in regulating peripheral NO_x- concentration.