BackgroundSchizophrenia, bipolar disorder, and major depression are devastating mental diseases, each with distinctive yet overlapping epidemiologic characteristics. Microarray and proteomics data have revealed genes which expressed abnormally in patients. Several single nucleotide polymorphisms (SNPs) and mutations are associated with one or more of the three diseases. Nevertheless, there are few studies on the interactions among the disease-associated genes and proteins.ResultsThis study, for the first time, incorporated microarray and protein-protein interaction (PPI) databases to construct the PPI network of abnormally expressed genes in postmortem brain samples of schizophrenia, bipolar disorder, and major depression patients. The samples were collected from Brodmann area (BA) 10 of the prefrontal cortex. Abnormally expressed disease genes were selected by t-tests comparing the disease and control samples. These genes were involved in housekeeping functions (e.g. translation, transcription, energy conversion, and metabolism), in brain specific functions (e.g. signal transduction, neuron cell differentiation, and cytoskeleton), or in stress responses (e.g. heat shocks and biotic stress).The diseases were interconnected through several “switchboard”-like nodes in the PPI network or shared abnormally expressed genes. A “core” functional module which consisted of a tightly knitted sub-network of clique-5 and -4s was also observed. These cliques were formed by 12 genes highly expressed in both disease and control samples.ConclusionsSeveral previously unidentified disease marker genes and drug targets, such as SBNO2 (schizophrenia), SEC24C (bipolar disorder), and SRRT (major depression), were identified based on statistical and topological analyses of the PPI network. The shared or interconnecting marker genes may explain the shared symptoms of the studied diseases. Furthermore, the “switchboard” genes, such as APP, UBC, and YWHAZ, are proposed as potential targets for developing new treatments due to their functional and topological significance.

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.

Supplementary data are available at Bioinformatics online.