Rewired Pathways and Disrupted Pathway Crosstalk in Schizophrenia Transcriptomes by Multiple Differential Coexpression Methods.

Hui Yu,Xiangning Chen,Peilin Jia,Jingchun Chen,Zhongming Zhao,Yan Guo

doi:10.3390/genes12050665

Abstract

Transcriptomic studies of mental disorders using the human brain tissues have been limited, and gene expression signatures in schizophrenia (SCZ) remain elusive. In this study, we applied three differential co-expression methods to analyze five transcriptomic datasets (three RNA-Seq and two microarray datasets) derived from SCZ and matched normal postmortem brain samples. We aimed to uncover biological pathways where internal correlation structure was rewired or inter-coordination was disrupted in SCZ. In total, we identified 60 rewired pathways, many of which were related to neurotransmitter, synapse, immune, and cell adhesion. We found the hub genes, which were on the center of rewired pathways, were highly mutually consistent among the five datasets. The combinatory list of 92 hub genes was generally multi-functional, suggesting their complex and dynamic roles in SCZ pathophysiology. In our constructed pathway crosstalk network, we found “Clostridium neurotoxicity” and “signaling events mediated by focal adhesion kinase” had the highest interactions. We further identified disconnected gene links underlying the disrupted pathway crosstalk. Among them, four gene pairs (PAK1:SYT1, PAK1:RFC5, DCTN1:STX1A, and GRIA1:MAP2K4) were normally correlated in universal contexts. In summary, we systematically identified rewired pathways, disrupted pathway crosstalk circuits, and critical genes and gene links in schizophrenia transcriptomes.

Highlights

Schizophrenia (SCZ) is one of the main mental disorders that disrupt both the physical and the social welfare of the affected subjects and their families
“signaling events mediated by focal adhesion kinase” (Figure 4A)
Due to the ethical standard for the collection of human brain tissue in research, transcriptome data have been very limited for schizophrenia (SCZ), and gene expression dysregulation mechanisms underlying SCZ remain elusive

Summary

Introduction

Schizophrenia (SCZ) is one of the main mental disorders that disrupt both the physical and the social welfare of the affected subjects and their families. SCZ transcriptome data, most were tied with microarrays [3,4], a technology gradually replaced by a more powerful approach, RNA-Seq. In recent years, a few studies conducted thorough analyses of SCZ brain transcriptomes, including original data analyses [5,6,7], meta-analyses [8,9], and re-analyses [10,11]. A few studies conducted thorough analyses of SCZ brain transcriptomes, including original data analyses [5,6,7], meta-analyses [8,9], and re-analyses [10,11] These works suggested probable implication with SCZ of individual biological processes, especially immune system [5,10,12], oxidative stress [11], and cytoskeleton remodeling [7]. SCZ and other neuropsychiatric disorders have been considered to have shared polygenic genetic architectures and dysregulated functional modules, while each of them has unique genetic components [7,16]

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