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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: 13.75). 10/2009; 66(10):1045-54. DOI: 10.1001/archgenpsychiatry.2009.139
Source: PubMed

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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    • "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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    • "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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