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ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.

The SNP rs2958182 was reported to be significantly associated with schizophrenia (SCZ) in Han Chinese. This study examined this SNP's associations with cognitive functions in 580 SCZ patients and 498 controls. Cognitive functions were assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-RC), the Attention Network Task (ANT), the Stroop task, the dot pattern expectancy (DPX), task and the N-back working memory task. Results showed significant or marginally significant interaction effects between genotype and diagnosis status on IQ (P ¼ 0.011) and attention-related tasks (ie, the forward digit span of WAIS-RC, P ¼ 0.005; the ANT conflict effect; P ¼ 0.020, and its ratios over mean reaction time (RT), P ¼ 0.036; the Stroop conflict effect, P ¼ 0.032, and its ratios over mean RT, P ¼ 0.062; and the DPX task's error rate under the BX condition, Po0.001, and the error rate of BX minus the error rate of AY (BX À AY), P ¼ 0.002). There were no such interaction effects on the measures of working memory (all P-values 40.05). Further analysis of the significant genotype-by-diagnosis interactions showed that the risk (T) allele was associated with better performance on cognitive tasks in patients but with worse performance in controls. These results seem to indicate that the association between this SNP and selected cognitive functions may be of an inverted U-shaped pattern. Future research is needed to replicate these results and to explore the biochemical mechanisms behind this association.

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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.