Zhang Zhifang, Chen Xiongying, Yu Ping, Zhang Qiumei, Sun Xiaochen, Gu Huang, Zhang Hao, Zhai Jinguo, Chen Min, Du Boqi, Deng Xiaoxiang, Ji Feng, Wang Chuanyue, Xiang Yutao, Li Dawei, Wu Hongjie, Li Jun, Dong Qi, Chen Chuansheng
1] State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China [2] Center for Collaboration and Innovation in Brain and Learning Sciences, Beijing Normal University, Beijing, China.
School of Mental Health, Jining Medical University, Jining, Shandong Province, P.R. China.
Neuropsychopharmacology. 2015 May;40(6):1383-94. doi: 10.1038/npp.2014.323. Epub 2014 Dec 10.
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=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 five 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 three 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 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.
一氧化氮（NO）作为一种气态神经递质，已被认为与精神分裂症的发病机制有关。相应地，人们发现编码主要产生NO的酶——一氧化氮合酶1（NOS1）的基因存在多种多态性，这些多态性会增加患精神分裂症的风险。本研究探讨了NOS1基因多态性在认知功能及相关神经机制中的作用。首先，我们选取了580例精神分裂症患者和720例健康对照作为样本，发现rs3782206基因型对1-back任务（P = 0.005）、2-back任务（P = 0.049）、点模式预期（DPX）任务的AY条件（P = 0.001）以及注意网络（ANT）测试的冲突效应（反应时差异P < 0.001，反应时比率P = 0.002）有主要影响，并且与诊断在DPX的BX条件（P = 0.009）、DPX的AY条件（P < 0.001）以及Stroop冲突效应（反应时差异P = 0.003，反应时比率P = 0.038）上存在交互作用。简单效应分析进一步表明，rs3782206的精神分裂症风险等位基因（T）与患者在五项测量指标上的较差表现相关（1-back，P = 0.025；BX，P = 0.017；AY，P < 0.001；ANT冲突效应（反应时差异），P = 0.005；Stroop冲突效应（反应时差异），P = 0.019），以及与对照组在三项测量指标上的较差表现相关（2-back任务，P = 0.042；ANT冲突效应（反应时差异），P = 0.013；ANT冲突效应（反应时比率），P = 0.028）。然后，我们选取了另一组78例健康对照样本，研究rs3782206与N-back任务和Stroop任务期间脑激活模式之间的关联。全脑分析发现，风险等位基因携带者在两项任务中右侧额下回（IFG）的激活均减少。最后，我们在三种条件下（N-back任务、Stroop任务和静息状态）检测了从右侧IFG到背外侧前额叶皮层（DLPFC）和前扣带回皮层的功能连接。结果显示，风险等位基因携带者主要在Stroop任务和静息状态下与DLPFC的连接减少。综上所述，本研究结果强烈表明rs3782206处的NOS1基因多态性与认知功能及其在IFG的神经基础之间存在联系。这些结果对于我们理解NOS1基因多态性与精神分裂症之间关联的神经机制具有重要意义。
