Influence of NOS1 on Verbal Intelligence and Working Memory in Both Patients With Schizophrenia and Healthy Control Subjects

Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity Health Sciences Bldg, St James's Hospital, Dublin 8, Ireland.
Archives of general psychiatry (Impact Factor: 14.48). 10/2009; 66(10):1045-54. DOI: 10.1001/archgenpsychiatry.2009.139
Source: PubMed


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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    • "Reif and colleagues (2011) also conducted an fNIRS study on rs41279104 and found that it played a significant role in prefrontal cortex during a verbal fluency task (working memory). For another SNP, rs6490121, Donohoe et al. (2009) found that it was significantly associated with working memory, but not attentional control in two independent samples. The same group of researchers also conducted an fMRI study (Rose et al, 2012) with a spatial working memory task on 48 healthy controls and found that the risk allele carriers exhibited altered activation at the prefrontal cortex. "
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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 · 7.05 Impact Factor
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    • "In addition, Kawohl et al. (2008) demonstrated that rs41279104 risk allele carriers had decreased loudness dependence of auditory evoked potentials, which is a functional marker of serotonergic transmission, arguing for a connection between the NO and serotonin systems as also shown on the protein and the neuronal network (Kiss and Vizi, 2001) level. Also, the GWAS risk SNP rs6490121 was shown to be functional in respect to general intelligence, working memory and visual sensory processing as measured by the electroencephalogram event-related P1 response (Donohoe et al., 2009; O'Donoghue et al., 2012). Most of these effects could also be observed in healthy controls, and not only patients. "
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    ABSTRACT: NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2013; 24(1). DOI:10.1016/j.euroneuro.2013.09.005 · 4.37 Impact Factor
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    • "In conclusion, significant differences could be shown for activation of the prefrontal cortex for the different alleles of the NOS1 ex1f-VNTR, therefore adding functional imaging data to reports by Donohoe et al. (2009) who demonstrated association findings with a single nucleotide polymorphism, rs6490121. Taken together, these findings therefore underline the importance of NOS-I in cognition and suggest that the modulation of cognitive functions through NO is far more widespread than previously thought. "
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    ABSTRACT: Nitric oxide (NO) synthase produces NO, which serves as first and second messenger in neurons, where the protein is encoded by the NOS1 gene. 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. We therefore investigated the influence of NOS1 ex 1f-VNTR on working memory function as reflected by both behavioral measures and prefrontal oxygenation. We hypothesized that homozygous short allele carriers exhibit altered brain oxygenation in task-related areas, namely the dorsolateral and ventrolateral prefrontal cortex and the parietal cortex. To this end, 56 healthy subjects were stratified into a homozygous long allele group and a homozygous short allele group comparable for age, sex and intelligence. All subjects completed a letter n-back task (one-, two-, and three-back), while concentration changes of oxygenated (O(2)Hb) hemoglobin in the prefrontal cortex were measured with functional near-infrared spectroscopy (fNIRS). We found load-associated O(2)Hb increases in the prefrontal and parts of the parietal cortex. Significant load-associated oxygenation differences between the two genotype groups could be shown for the dorsolateral prefrontal cortex and the parietal cortex. Specifically, short allele carriers showed a significantly larger increase in oxygenation in all three n-back tasks. This suggests a potential compensatory mechanism, with task-related brain regions being more active in short allele carriers to compensate for reduced NOS1 expression.
    NeuroImage 05/2011; 57(4):1617-23. DOI:10.1016/j.neuroimage.2011.05.034 · 6.36 Impact Factor
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