Influence of NOS1 on verbal intelligence and working memory in both patients with schizophrenia and healthy control subjects.
ABSTRACT Human and animal studies have implicated the gene NOS1 in both cognition and schizophrenia susceptibility.
To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects.
A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample.
Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained.
Patients with DSM-IV-diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality.
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. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also.
NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.
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ABSTRACT: NO is a gaseous transmitter produced by nitric oxide synthases (NOSs). The neuronal isoform (NOS-I, encoded by NOS1) is the main source of NO in the CNS. Animal studies suggest that nitrinergic dysregulation may lead to behavioral abnormalities. Unfortunately, the large number of animal studies is not adequately reflected by publications concerning humans. These include postmortem studies, determination of biomarkers, and genetic association studies. Here, we review the evidence for the role of NO in psychiatric disorders by focusing on the human NOS1 gene as well as biomarker studies. Due to the complex regulation of NOS1 and the varying function of NOS-I in different brain regions, no simple, unidirectional association is expected. Rather, the "where, when and how much" of NO formation is decisive. Present data, although still preliminary and partially conflicting, suggest that genetically driven reduced NO signaling in the prefrontal cortex is associated with schizophrenia and cognition. Both NOS1 and its interaction partner NOS1AP have a role therein. Also, reduced NOS1 expression in the striatum determined by a length polymorphism in a NOS1 promoter (NOS1 ex1f-VNTR) goes along with a variety of impulsive behaviors. An association of NOS1 with mood disorders, suggested by animal models, is less clear on the genetic level; however, NO metabolites in blood may serve as biomarkers for major depression and bipolar disorder. As the nitrinergic system comprises a relevant target for pharmacological interventions, further studies are warranted to elucidate the pathophysiology of mental disorders, but also to evaluate NO function as a biomarker. This article is protected by copyright. All rights reserved.Genes Brain and Behavior 01/2015; 14(1). DOI:10.1111/gbb.12193 · 3.51 Impact Factor
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ABSTRACT: Evidence for involvement of DNA methylation in psychosis forms the focus of this perspective. Of interest are results from two independent sets of experiments including rats treated with antipsychotic drugs and monozygotic twins discordant for schizophrenia. The results show that DNA methylation is increased in rats treated with antipsychotic drugs, reflecting the global effect of the drugs. Some of these changes are also seen in affected schizophrenic twins that were treated with antipsychotics. The genes and pathways identified in the unrelated experiments are relevant to neurodevelopment and psychiatric disorders. The common cause is hypothesized to be aberrations resulting from medication use. However, this needs to be established by future studies that address the origin of methylation changes in psychosis.Epigenomics 02/2015; 7(1):67-74. DOI:10.2217/epi.14.66 · 5.22 Impact Factor
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ABSTRACT: Nitric oxide (NO), a gaseous neurotransmitter, has been implicated in the pathogenesis of schizophrenia. Accordingly, several polymorphisms of the gene that codes for the main NO-producing enzyme, the Nitric oxide synthase 1 (NOS1), have been found convey a risk for schizophrenia. This study examined the role of NOS1 gene polymorphisms in cognitive functions and related neural mechanism. First, with a sample of 580 schizophrenia patients and 720 healthy controls, we found that rs3782206 genotype had main effects on the 1-back task (P=0.005), the 2-back task (P=0.049), the AY condition of the dot-pattern expectancy [DPX] task (P=0.001), and the conflict effect of the attention network [ANT] test (P< 0.001 for RT differences and P=0.002 for RT ratio) and interaction effects with diagnosis on the BX condition of the DPX (P=0.009), the AY condition of the DPX (P< 0.001), and the Stroop conflict effect (P=0.003 for RT differences and P=0.038 for RT ratio). Simple effect analyses further showed that the schizophrenia risk allele (T) of rs3782206 was associated with poorer performance in 5 measures for the patients (1-back, P=0.025; BX, P=0.017; AY, P< 0.001; ANT conflict effect [RT differences], P=0.005; Stroop conflict effect [RT differences], P=0.019) and 3 measures for the controls ( for the 2-back task, P=0.042; for the ANT conlict effect [RT differences], P=0.013; for the ANT conflict effect [RT ratios], P=0.028). Then, with a separate sample of 78 healthy controls, we examined the association between rs3782206 and brain activation patterns during the N-back task and the Stroop task. Whole brain analyses found that the risk allele carriers showed reduced activation at the right inferior frontal gyrus (IFG) during both tasks. Finally, we examined functional connectivity seeded from the right IFG to the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) under three conditions (the N-back task, the Stroop task, and the resting-state). Results showed reduced connectivity with the DLPFC for the risk allele carriers mainly in the Stroop task and the resting-state. Taken together, results of this study strongly suggested a link between NOS1 gene polymorphism at rs3782206 and cognitive functions and their neural underpinnings at the IFG. These results have important implications for our understanding of the neural mechanism underlying the association between NOS1 gene polymorphism and schizophrenia.Neuropsychopharmacology accepted article preview online, 10 December 2014. doi:10.1038/npp.2014.323.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2014; 40(6). DOI:10.1038/npp.2014.323 · 7.83 Impact Factor