title: 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=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.
authors.affiliation: 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.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiongying
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.affiliation: School of Mental Health, Jining Medical University, Jining, Shandong Province, P.R. China.
authors.forename: Qiumei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Huang
authors.initials: H
authors.lastname: Gu
authors.affiliation: 1] College of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin, P. R. China [2] Key Laboratory of Opto-electronics Information Technology, Ministry of Education, Tianjin, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Mental Health, Jining Medical University, Jining, Shandong Province, P.R. China.
authors.forename: Jinguo
authors.initials: J
authors.lastname: Zhai
authors.affiliation: School of Mental Health, Jining Medical University, Jining, Shandong Province, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Boqi
authors.initials: B
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Deng
authors.affiliation: School of Mental Health, Jining Medical University, Jining, Shandong Province, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ji
authors.affiliation: Beijing Anding Hospital, Beijing, China.
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1] Beijing Anding Hospital, Beijing, China [2] Faculty of Health Sciences, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.affiliation: Shengli Hospital of Shengli Petroleum Administration Bureau, Dongying, Shandong province, P.R. China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qi
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Psychology and Social Behavior, University of California, Irvine, CA, USA.
authors.forename: Chuansheng
authors.initials: C
authors.lastname: Chen
mesh_terms: D000328:Adult; D001931:Brain Mapping; D005260:Female; D007839:Functional Laterality; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D009483:Neuropsychological Tests; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011930:Reaction Time / Q000235:genetics; D012146:Rest; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D057190:Stroop Test
chemical_list: C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I