Evidence for the Contribution of NOS1 Gene Polymorphism (rs3782206) to Prefrontal Function in Schizophrenia Patients and Healthy Controls

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 to 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 ¼ 0.005), the 2-back task (P ¼ 0.049), the AY condition of the dot-pattern expectancy (DPX) task (P ¼ 0.001), and the conflict effect of the attention network (ANT) test (Po0.001 for RT differences and P ¼ 0.002 for RT ratio) and interaction effects with diagnosis on the BX condition of the DPX (P ¼ 0.009), the AY condition of the DPX (Po0.001), and the Stroop conflict effect (P ¼ 0.003 for RT differences and P ¼ 0.038 for RT ratio). Simple effect analyses further showed that the schizophrenia risk allele (T) of rs3782206 was associated with poorer performance in five measures for the patients (1-back, P ¼ 0.025; BX, P ¼ 0.017; AY, Po0.001; ANT conflict effect (RT differences), P ¼ 0.005; Stroop conflict effect (RT differences), P ¼ 0.019) and three measures for the controls ( for the 2-back task, P ¼ 0.042; for the ANT conlict effect (RT differences), P ¼ 0.013; for the ANT conflict effect (RT ratios), P ¼ 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 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.

Functional connectivity measures as schizophrenia intermediate phenotypes: advances, limitations, and future directions

“…While no associations have been found between the first two circuits and schizophrenia risk genes, a link between PFC-PFC coupling and genetic candidate variants has been established in several studies [48,65], suggesting the value of this phenotype for genetic studies. Moreover, impaired cerebellum connectivity has also been widely reported in the literature.…”

“…Cognitive control is the assessment of brain's executive functions such as conflict monitoring and error detection, and can be examined by various established fMRI tasks, for example, a Flanker task [46,47] or a Stroop task [48]. Three potential connectivity intermediate phenotypes for cognitive control have been reported in the literature.…”

“…The first phenotype consists of connectivity alterations within the PFC, where decreased coupling has been found in both schizophrenia patients and relatives [49 ]. Furthermore, this abnormality has been recently identified in risk variant carriers of NOS1, a candidate gene for schizophrenia [48]. The second finding is the effective connectivity from the ACC to the DLPFC.…”

Effect of rs1063843 in theCAMKK2gene on the dorsolateral prefrontal cortex

“…In this study, we explored the neural mechanism of the association between rs1063843 and cognitive function using functional magnetic resonance imaging (fMRI) data obtained from 84 subjects during three tasks: a Stroop task, an N-back task, and a delay discounting task (DDT). These tasks measure attentional executive control, working memory, and decision making, respectively, all of which have been reported to activate the DLPFC in previous fMRI studies Callicott et al, 2003;Zhang et al, 2015]. We hypothesized that the rs1063843 risk allele would affect the activation of the DLPFC during all tasks.…”

Corrected QT Interval Prolongation in Psychopharmacological Treatment and Its Modulation by Genetic Variation

“…Another study, however, failed to replicate rs12029454 association with QT c but this may be due in part to the different (Chinese vs. European) ancestry of the study populations [32]. Intriguingly, NOS1AP variants have been also associated with schizophrenia cognitive functions [33] which may allow the subgrouping of subjects with specific deficits [34] in order to reach a carefully personalized treatment.…”