One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia.
Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia.
Overall, our meta-analysis demonstrates the significance of NOS1 genetic variants that are functionally associated with cognitive and neuropsychiatric symptoms of schizophrenia.
Amongst the most promising candidate molecules for schizophrenia are neuronal nitric oxide (NO) synthase (NOS-I, also known as nNOS) and its adapter protein NOS1AP (previously named CAPON).
Accordingly, several polymorphisms of the gene that codes for the main NO-producing enzyme, the nitric oxide synthase 1 (NOS1), have been found to convey a risk for schizophrenia.
This region has been of significant interest to psychiatric genetics as it contains the Darier's disease locus and other proposed susceptibility genes (e.g., DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations.
The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes.
While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function.
Recently, the promoter region of nitric oxide (NO) synthase-I (NOS-I, encoded by the gene NOS1), impacting on prefrontal glutamate transmission, has repeatedly been associated with schizophrenia.
A functional variable number of tandem repeats (VNTR) polymorphism in the promoter region of the alternative first exon 1f of NOS1 is associated with various functions of human behavior, for example increased impulsivity, while another, non-functional variant was linked to decreased verbal working memory and a heightened risk for schizophrenia.
Genetic variations of NOS1 have also been associated with schizophrenia, and differential expression of NOS1 was observed in the postmortem brain of schizophrenic patients.
In conclusion, understanding the molecular mechanisms underlying the over-expression of specific NOS1 isoforms, which is unique to schizophrenia, may assist in identifying targets for new drugs.
A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups.
We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs2682826, and rs6490121) in NOS1 that were positively associated with schizophrenia in previous studies.
Our results strongly support a previous hypothesis that NOS1 contributes to the genetic risk of schizophrenia and suggest that further research on more NOS1 variants and its regular elements are warranted.
Our results strongly support a previous hypothesis that NOS1 contributes to the genetic risk of schizophrenia and suggest that further research on more NOS1 variants and its regular elements are warranted.
Altered expression of genes involved in GABAergic transmission and neuromodulation of granule cell activity in the cerebellum of schizophrenia patients.
Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.
Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia.