Rampino Antonio, Walker Rosie May, Torrance Helen Scott, Anderson Susan Maguire, Fazio Leonardo, Di Giorgio Annabella, Taurisano Paolo, Gelao Barbara, Romano Raffaella, Masellis Rita, Ursini Gianluca, Caforio Grazia, Blasi Giuseppe, Millar J Kirsty, Porteous David John, Thomson Pippa Ann, Bertolino Alessandro, Evans Kathryn Louise
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom; Department of Neuroscience and Sense Organs, University of Bari, Bari, Italy.
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
PLoS One. 2014 Jun 18;9(6):e99892. doi: 10.1371/journal.pone.0099892. eCollection 2014.
Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.
认知功能障碍是精神分裂症表型的核心。遗传和功能研究表明，精神分裂症断裂基因1（DISC1）是精神分裂症及相关精神疾病的主要候选基因，与认知功能有关。在精神分裂症中已发现DISC1及其相互作用蛋白的表达改变。因此，DISC1相互作用组基因的表达失调可能通过破坏正常认知功能所需的分子系统而导致精神分裂症易感性。在此，我们测量了63名对照受试者血液中DISC1及其相互作用蛋白的RNA表达水平。使用神经精神测试评估认知功能，并使用功能磁共振成像评估在N-back工作记忆任务期间前额叶皮质区域的活动，该任务在精神分裂症中是异常的。评估了基因表达水平之间的成对相关性以及基因表达水平与认知功能和N-back诱发的大脑活动之间的关系。最后，比较了63名对照受试者和69名精神分裂症患者中DISC1、AKAP9、FEZ1、NDEL1和PCM1的表达水平。我们发现DISC1相互作用组基因在健康个体的血液中显示出相关表达。几个相互作用组成员的表达水平与认知表现和前额叶皮质中N-back诱发的活动相关。此外，与健康对照相比，精神分裂症患者中DISC1和NDEL1的表达降低。我们的研究结果突出了DISC1相互作用组基因的协调表达对正常认知功能的重要性，并表明DISC1和NDEL1表达失调可能部分通过破坏前额叶皮质依赖的认知功能而导致精神分裂症易感性。
