Yin Jingwen, Ma Guoda, Luo Shucun, Luo Xudong, He Bin, Liang Chunmei, Zuo Xiang, Xu Xusan, Chen Qing, Xiong Susu, Tan Zhi, Fu Jiawu, Lv Dong, Dai Zhun, Wen Xia, Zhu Dongjian, Ye Xiaoqing, Lin Zhixiong, Lin Juda, Li You, Chen Wubiao, Luo Zebin, Li Keshen, Wang Yajun
Department of Psychiatry, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Center for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Macao SAR, China.
Front Mol Neurosci. 2021 Nov 1;14:739526. doi: 10.3389/fnmol.2021.739526. eCollection 2021.
This research aimed to investigate the role of glyoxalase 1 (Glo-1) polymorphisms in the susceptibility of schizophrenia. Using the real-time polymerase chain reaction (PCR) and spectrophotometric assays technology, significant differences in Glo-1 messenger ribonucleic acid (mRNA) expression ( = 3.98 × 10) and enzymatic activity ( = 1.40 × 10) were found in peripheral blood of first-onset antipsychotic-naïve patients with schizophrenia and controls. The following receiver operating characteristic (ROC) curves analysis showed that Glo-1 could predict the schizophrenia risk ( = 4.75 × 10 in mRNA, = 1.43 × 10 in enzymatic activity, respectively). To identify the genetic source of Glo-1 risk in schizophrenia, Glo-1 polymorphisms (rs1781735, rs1130534, rs4746, and rs9470916) were genotyped with SNaPshot technology in 1,069 patients with schizophrenia and 1,023 healthy individuals. Then, the impact of risk polymorphism on the promoter activity, mRNA expression, and enzymatic activity was analyzed. The results revealed significant differences in the distributions of genotype ( = 0.020, false discovery rate (FDR) correction) and allele ( = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity ( = 0.016), mRNA expression, and enzymatic activity = 0.001 and = 0.015, respectively, GG vs. TT, in peripheral blood of patients with schizophrenia) of Glo-1. The expression quantitative trait locus (eQTL) findings were followed up with the resting-state functional magnetic resonance imaging (fMRI) analysis. The TT genotype of rs1781735, associated with lower RNA expression in the brain ( < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia ( < 0.001). In aggregate, this study for the first time demonstrates how the genetic and biochemical basis of Glo-1 polymorphism culminates in the brain function changes associated with increased schizophrenia risk. Thus, establishing a combination of multiple levels of changes ranging from genetic variants, transcription, protein function, and brain function changes is a better predictor of schizophrenia risk.
本研究旨在探讨乙二醛酶1（Glo-1）基因多态性在精神分裂症易感性中的作用。采用实时聚合酶链反应（PCR）和分光光度测定技术，发现在首发未使用过抗精神病药物的精神分裂症患者和对照组的外周血中，Glo-1信使核糖核酸（mRNA）表达（= 3.98×10）和酶活性（= 1.40×10）存在显著差异。随后的受试者工作特征（ROC）曲线分析表明，Glo-1可以预测精神分裂症风险（mRNA中= 4.75×10，酶活性中= 1.43×10）。为了确定精神分裂症中Glo-1风险的遗传来源，采用SNaPshot技术对1069例精神分裂症患者和1023名健康个体的Glo-1基因多态性（rs1781735、rs1130534、rs4746和rs9470916）进行基因分型。然后，分析风险多态性对启动子活性、mRNA表达和酶活性的影响。结果显示，rs1781735的基因型分布（= 0.020，错误发现率（FDR）校正）和等位基因分布（= 0.020，FDR校正）存在显著差异，其中G>T突变显著降低了Glo-1在精神分裂症患者外周血中的启动子活性（= 0.016）、mRNA表达和酶活性（GG与TT相比，分别为= 0.001和= 0.015）。通过静息态功能磁共振成像（fMRI）分析对表达数量性状位点（eQTL）的研究结果进行了跟进。rs1781735的TT基因型与大脑中较低的RNA表达相关（<0.05），在精神分裂症患者的左侧额中回显示神经元激活减少（<0.001）。总的来说，本研究首次证明了Glo-1基因多态性的遗传和生化基础如何最终导致与精神分裂症风险增加相关的脑功能变化。因此，建立从基因变异、转录、蛋白质功能到脑功能变化等多个层面变化的组合，是精神分裂症风险的更好预测指标。
