Peripheral Blood Metabolome And Transcriptome Studies In Schizophrenia

PART1 SCREENING OF PLASMA BIOMARKERS IN PATIENTS WITH SCHIZOPHRENIA BASED ON TARGETED METABOLOMICSBackground and objective:Schizophrenia is a serious psychiatric disorder and metabolic disorders in patients are important causative factors of the disease.The aim of this study was to identify plasma lipid and amino acid biomarkers in schizophrenia patients using targeted metabolomics.Methods:22 amino acids and 160 lipids and their related metabolites in plasma which from 76 patients with schizophrenia and 50 healthy controls were analyzed using the LC-MS-based multiple reaction monitoring(MRM)metabolomics approach.The drug-na?ve SCZ patients were used as a training set to discovery biomarkers,and the SCZ patients with medication were used as a test set to validate the performance of the biomarkers panel.On the basis of differentially expressed metabolites,the potential biomarkers panel was further screened by binary logistic regression analysis,and the validity and sensitivity of the biomarkers panel were evaluated using the receiver operating characteristic curve(ROC).Results:Based on the training set,we found 19 metabolites showing abnormal expression(False discovery rate,FDR < 0.05),including 1 amino acid and 18 lipids and their related metabolites.A biomarkers panel containing four metabolites(phosphatidylcholine 32:1,phosphatidylethanolamine 34:2,phosphatidylethanolamine(O-34:3)and aspartic acid)was selected by binary logistic regression analysis.Furthermore,it was used to draw the receiver operating characteristic curve and calculate the area under curve(AUC).Our results indicated that the diagnostic biomarkers panel was effective in distinguishing patients with schizophrenia form healthy controls(AUC = 0.948,95% CI: 0.912~0.985)and had more prominent performance in identifying SCZ patients with medication from healthy controls(AUC = 0.963,95% CI: 0.926~1.000).Conclusions:Plasma lipids and amino acids showed significant dysregulation in SCZ.And phosphatidylcholine 32:1,phosphatidylethanolamine 34:2,phosphatidylethanolamine(O-34:3)and aspartic acid could effectively differentiate patients with schizophrenia from healthy controls.PART2 ABNORMAL PHOSPHOLIPID METABOLIC PATHWAYS IN PERIPHERAL BLOOD OF PATIENTS WITH SCHIZOPHRENIA REVEALED BY TRANSCRIPTOMICSBackground:Schizophrenia is a serious psychiatric disorder caused by synergistic genetic and environmental factors.We found significant abnormalities of lipid metabolism in patients with schizophrenia in the first part of our study.However,it's upstream regulatory mechanisms are unclear.Objective:Combining the brain transcriptomic data form GEO dataset and our peripheral blood transcriptomic data in patients with SCZ to search for upstream regulatory mechanisms of abnormal lipid metabolism in patients with SCZ.Methods:1.m RNA expression of peripheral blood mononuclear cells(PBMC)from 10 patients with SCZ and 20 healthy controls was measured by second-generation transcriptional sequencing technology,meanwhile we combined with the GSE80655 public dataset of brain transcriptome of patients with SCZ for bioinformatics analysis.2.The general liner model functions are used for test differential expression based on likelihood ratio tests.3.Weighted gene co-expression network analysis(WGCNA),preservation and pathway enrichment analysis were used to explore similar gene expression patterns in central and peripheral blood,and to search for upstream regulatory genes of abnormal lipid metabolism in patients with SCZ.4.Real-time fluorescence quantitative polymerase chain reaction(qPCR)was used to validate differentially expressed genes in the lipid metabolism signaling pathway in schizophrenia.Results:1.542 differentially expressed genes were identified in PBMC of patients with schizophrenia(P < 0.05,Fold change > 1.3).2.Based on the differentially expressed genes,WGCNA and preservation analysis,we found that the five differentially expressed gene clusters had similar expression patterns in the central and peripheral.3.By functional enrichment analysis,we found the above 5 differentially expressed gene clusters were mainly enriched in phosphatidylethanolamine biosynthesis,phosphatidylcholine biosynthesis,phospholipase signaling pathway,mitochondrial dysfunction,and oxidative phosphorylation pathways.4.The differentially expressed genes within key pathways were validated by q PCR,including phospholipase A and acyltransferase 3(PLAAT3),phospholipase A and acyltransferase 4(PLAAT4),phospholipase D2(PLD2),cytochrome C oxidase subunit 7c(COX7C),NADH dehydrogenase 1 alpha subcomplex assembly factor 2(NDUFAF2)and ATP synthase membrane subunit e(ATP5ME)with significant differences(P < 0.05).Conclusions:In the present study,we found that the expression patterns of several signaling pathways in peripheral blood in schizophrenia are similar to those in the central nervous,among which phospholipase D2(PLD2)and choline kinase A(CHKA)may be the key regulatory gene for abnormal phosphatidylethanolamine and phosphatidylcholine metabolism in schizophrenia.