Systematic Study to Unveil Novel Biomarkers, Regulatory Pathways and Exploring Therapeutic Targets for Schizophrenia Using Next Generation Sequencing Data Analysis and In Silico Drug Design

Schizophrenia is a common mental disease leading threat to human health around the world. Here we aimed to explore new biomarkers and potential therapeutic targets in schizophrenia via adopting integrated bioinformatics tools. Next generation sequencing (NGS) dataset was obtained from the Gene Expression Omnibus (GEO) database and analyzed in limma package in R bioconductor to identify differentially expressed genes (DEGs). Gene Ontology (GO) and pathway enrichment analyses of DEGs were performed via g:Profiler. A network of protein-protein interactions (PPIs) was constructed. Cytoscape was used to visualize hub genes and critical modules based on the PPI network. A miRNA-hub gene regulatory network, TF-hub gene regulatory network and drug-hub gene interaction network for the identified hub genes was built using the miRNet and NetworkAnalyst databases. We used receiver operating characteristic (ROC) curve to assess the diagnostic efficacy of hub genes. We conducted molecular docking and ADMET with hub genes and corresponding active molecules. In total, 955 DEGs, containing 478 up-regulated and 477 down-regulated genes, were identified. The DEGs were mainly enriched in biological regulation, nervous system development, interferon signaling and neuronal system. Based on the data of protein-protein interaction (PPI), the top 10 hub genes (5 up regulated and 5 down regulated) were ranked, including HLA-B, NEDD4, ARF6, SP3, RPS28, MYC, LRRK2, SIRT2, ERBB3 and MAPT.These hub emerged as identifying genes for schizophrenia, validated through a ROC analysis. The miRNA-hub gene regulatory network and TF-hub gene regulatory network showed that hsa-mir-212-3p, hsa-mir-191-3p, STAT3 and SOX9 might play an important role in the pathogenesis of schizophrenia. The drug-hub gene interaction network showed that Quercetin, Masoprocol, Ziprasidone and Bufuralolpredicted therapeutic drugs for the chizophrenia. Molecular docking analysis revealed that 10a, 10b, and 10c were the main active compounds with good binding activities to the two hub gene targets. 10 hub genes (HLA-B, NEDD4, ARF6, SP3, RPS28, MYC, LRRK2, SIRT2, ERBB3 and MAPT) have been elucidated in this investigation, and these biomarkers might be helpful in the diagnosis and therapy of patients with schizophrenia.