Whole Transcriptome Sequencing Identified CircRNA Profiles and the Related Networks in Schizophrenia

Abstract

Schizophrenia (SCZ) is a complex psychiatric syndrome with uncertain etiology. This study aimed to uncover the expression profiles and related regulatory networks of circular RNA (circRNA) in SCZ. Whole transcriptome sequencing was performed to assess the expression profiles of circRNAs and microRNAs (miRNAs) in the peripheral blood of three patients with SCZ and three healthy controls. Five circRNAs were validated by quantitative real-time PCR (RT-qPCR). TargetScan, RNAhybrid, and miRanda were performed to predict the target miRNAs of the top 10 dysregulated circRNAs. MiRTarBase was applied to predict the target mRNAs of miRNAs to construct circRNA-miRNA-mRNA (ceRNA) networks. CatRAPID and StarBase were used to predict the target RNA-binding proteins (RBPs) of circRNAs to construct circRNA-RBP networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the potential functions of the maternal genes of circRNAs and target mRNAs. In total, 450 circRNAs and 160 miRNAs were found to be significantly differentially expressed, with hsa_circ_0003999 and hsa_circ_0030042 being significantly different between patients with SCZ and healthy controls (P < 0.05). The PI3K-AKT, MAPK, and cell cycle pathways were predicted to be associated with SCZ. GO analysis showed that focal adhesion was related to SCZ. The ceRNA networks, especially hsa_circ_0006151/hsa-miR-4685-3p/ZBTB16, hsa_circ_0000008/hsa-miR-1976/ZBTB16, and the hsa_circ_0007963/hsa-miR-3127-3p/UBE2K axes have the greatest probability of being involved in the pathophysiology of SCZ. The RBP networks, FXR1, FXR2, DGCR8, XRN2, FMR1, and QKI were the RBPs associated with SCZ. In conclusion, the circRNAs, ceRNAs, and RBP network expression patterns and related pathways indicate the potential role of circRNAs in the pathogenesis and development of SCZ.

Keywords: Schizophrenia; circRNA; circRNA–RBP network; circRNA–miRNA–mRNA network.