Glyoxalase 1 Confers Susceptibility to Schizophrenia: From Genetic Variants to Phenotypes of Neural Function.

Jingwen Yin,Susu Xiong,Xiaoqing Ye,Shucun Luo,Dongjian Zhu,You Li,Juda Lin,Bin He,Qing Chen,Chunmei Liang,Guoda Ma,Xudong Luo,Yajun Wang,Xiang Zuo,Keshen Li,Dong Lv,Jiawu Fu,Xusan Xu,Wubiao Chen,Zhen Luo ,Xin Wen ,Zhongqiu Lin ,Zhi Yuan Tan ,Zhongmin Dai

doi:10.3389/fnmol.2021.739526

Abstract

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 (P = 3.98 × 10−5) and enzymatic activity (P = 1.40 × 10−6) 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 (P = 4.75 × 10−6 in mRNA, P = 1.43 × 10−7 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 (P = 0.020, false discovery rate (FDR) correction) and allele (P = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity (P = 0.016), mRNA expression, and enzymatic activity (P = 0.001 and P = 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 (P < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia (P < 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.

Highlights

Schizophrenia is a devastating and complex neurodevelopmental disorder with highly heterogeneous and multifaceted clinical manifestations (Cannon, 1996; Allen et al, 2008)
We demonstrated that a novel functional Single Nucleotide Polymorphism (SNP) in the promoter of the Glyoxalase 1 (Glo-1) gene is associated with the risk of schizophrenia, and a large proportion of individuals with schizophrenia are homozygous for the rs1781735 T allele
We first reported the effect of the Glo-1 gene on the neural function of schizophrenia using a functional SNP as the proxy

Summary

Introduction

Schizophrenia is a devastating and complex neurodevelopmental disorder with highly heterogeneous and multifaceted clinical manifestations (Cannon, 1996; Allen et al, 2008). The variants in risk genes might lead to dysregulation of molecular pathways and aberrations in the structure and function of the brain, which could be reflected by the abnormalities in cognitive function, emotions, and behaviors (Owen et al, 2016; Klingler et al, 2021). To systematically understand how genes confer risks across these levels of schizophrenia will help to build a spectrum of abnormal states, predict vulnerable processes, design personalized diagnostic, and therapeutic tools (Klingler et al, 2021). Carbonyl stress is an abnormal metabolic state that results in the accumulation of dicarbonyl compounds, such as methylglyoxal (MG) and glyoxal (Miyata et al, 1999) leading to the eventual formation of advanced glycation end products (AGEs). The recent studies in animals and humans have demonstrated that enhanced carbonyl stress contributes to the onset of various neurological disorders, such as schizophrenia (Itokawa et al, 2018; Yoshioka et al, 2021), Parkinson’s disease (Kurz et al, 2011), Alzheimer’s disease (Kuhla et al, 2007; Frandsen et al, 2020; Lv et al, 2020), mood disorder (Fujimoto et al, 2008), autism (Junaid et al, 2004; Gabriele et al, 2014; Kovac et al, 2015), panic disorder (Politi et al, 2006), and anxiety behavior (Hovatta et al, 2005; Distler et al, 2012; Du et al, 2019)

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