Transcriptome alterations of mitochondrial and coagulation function in schizophrenia by cortical sequencing analysis

Abstract

BackgroundTranscriptome sequencing of brain samples provides detailed enrichment analysis of differential expression and genetic interactions for evaluation of mitochondrial and coagulation function of schizophrenia. It is implicated that schizophrenia genetic and protein interactions may give rise to biological dysfunction of energy metabolism and hemostasis. These findings may explain the biological mechanisms responsible for negative and withdraw symptoms of schizophrenia and antipsychotic-induced venous thromboembolism.We conducted a comparison of schizophrenic candidate genes from literature reviews and constructed the schizophrenia-mediator network (SCZMN) which consists of schizophrenic candidate genes and associated mediator genes by applying differential expression analysis to BA22 RNA-Seq brain data. The network was searched against pathway databases such as PID, Reactome, HumanCyc, and Cell-Map. The candidate complexes were identified by MCL clustering using CORUM for potential pathogenesis of schizophrenia.ResultsPublished BA22 RNA-Seq brain data of 9 schizophrenic patients and 9 controls samples were analyzed. The differentially expressed genes in the BA22 brain samples of schizophrenia are proposed as schizophrenia candidate marker genes (SCZCGs). The genetic interactions between mitochondrial genes and many under-expressed SCZCGs indicate the genetic predisposition of mitochondria dysfunction in schizophrenia. The biological functions of SCZCGs, as listed in the Pathway Interaction Database (PID), indicate that these genes have roles in DNA binding transcription factor, signal and cancer-related pathways, coagulation and cell cycle regulation and differentiation pathways.In the query-query protein-protein interaction (QQPPI) network of SCZCGs, TP53, PRKACA, STAT3 and SP1 were identified as the central "hub" genes. Mitochondrial function was modulated by dopamine inhibition of respiratory complex I activity. The genetic interaction between mitochondria function and schizophrenia may be revealed by DRD2 linked to NDUFS7 through protein-protein interactions of FLNA and ARRB2.The biological mechanism of signaling pathway of coagulation cascade was illustrated by the PPI network of the SCZCGs and the coagulation-associated genes. The relationship between antipsychotic target genes (DRD2/3 and HTR2A) and coagulation factor genes (F3, F7 and F10) appeared to cascade the following hemostatic process implicating the bottleneck of coagulation genetic network by the bridging of actin-binding protein (FLNA).ConclusionsIt is implicated that the energy metabolism and hemostatic process have important roles in the pathogenesis for schizophrenia. The cross-talk of genetic interaction by these co-expressed genes and reached candidate genes may address the key network in disease pathology. The accuracy of candidate genes evaluated from different quantification tools could be improved by crosstalk analysis of overlapping genes in genetic networks.

Transcriptome Analysis of Systems Biology for Schizophrenia

“…Recent developments of DNA sequencing technology and whole genome studies implicated that mutations play a vital role in the genetic architecture of schizophrenia and implicated in several molecular pathways, including chromatin regulation, activity-regulated cytoskeleton, postsynaptic density, and N-methyl-D-aspartate (NMDA) receptor, which are associated with schizophrenia [14]. Schizophrenia-network pathway complex analysis (SCZ-NPCA) has included enrichment analysis which demonstrates the role of the implicated pathways in schizophrenia, such as transcription activity, signaling pathway, cancer-related pathway, tumor suppression, coagulation, insulin secretion, cell cycle, cell diferentiation, and apoptosis [5].…”

“…There have been many studies focusing on the discovery of diferential expression of schizophrenic candidate genes and the construction of PPI networks and related pathways for the hope of a beter understanding of schizophrenia [5,[25][26][27][28]. Diferentially expressed disease genes from postmortem brain samples of schizophrenia reveal the overall relationships between maker genes and schizophrenia.…”

“…The diferentially expressed genes in the BA22 brain samples of schizophrenia are proposed as schizophrenia candidate marker genes (SCZCGs) [5]. For the exploration of modulation and regulation relations between schizophrenic hypermethylated promotors and diferential expression genes, we analyzed hypermethylation promotors and extended protein-protein interactions (PPIs) of SCZCGs to their level one interactions to construct the hypermethylation to diferential expression networks (HyDEN).…”

“…The genetic interactions and intermediate mediators among mitochondrial genes and many underexpressed SCZCGs indicate the genetic predisposition of mitochondria dysfunction in schizophrenia. The genetic interactions between mitochondria and schizophrenia may be revealed by the DRD2-NDUFS7 and the FLNA-ARRB2 interactions [5].…”

“…It contains 9,444,230 SNPs with sample size of 82,315, including 35,476 schizophrenia cases and 46,839 controls. Recent NGS researches including comprehensive and collective postmortem brain sample data come from [5].…”