4.6 Article

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

期刊

GENES
卷 12, 期 5, 页码 -

出版社

MDPI
DOI: 10.3390/genes12050665

关键词

differential co-expression; pathway crosstalk; schizophrenia; PSMC6

资金

  1. National Institutes of Health [R01LM012806]
  2. Chair Professorship for Precision Health funds
  3. Cancer Center Support Grant from the National Cancer Institute [P30CA118100]
  4. Bioinformatics Shared Resources at the Comprehensive Cancer Center at the University of New Mexico

向作者/读者索取更多资源

Through transcriptomic analysis of schizophrenia, we systematically identified rewired pathways, disrupted pathway crosstalk circuits, and key genes and gene links in the disease.
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.

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