Study Of Targeted Screening Blood-based Diagnostic Biomarkers In Schizophrenia

Schizophrenia is a chronic,debilitating and complex psychiatric disorder,whose prevalence rate is about 0.5-1% in different cultural geographical regions of the world.Due to unknown pathogenesis,serious complications and adverse effects from violence of patients,schizophrenia has become a serious public health and social problem.Currently,the clinical diagnostics of the disease still relies on the subjective judgment of psychiatrists.However,due to the dual impact of their own and the environmental factors,the levels of professional skills among psychiatrists are uneven.Hence,the phenomenon of misdiagnosis and missed diagnosis of schizophrenia is very common.Therefore,it is urgent to discover objective molecular diagnostic methods to assist clinicians on the inquiry to improve the objectivity,accuracy,and consistency of diagnosis,providing the basis for the more targeted treatment later.Biological biomarkers,i.e.biomarkers,are characteristics that can be objectively measured and evaluated as indicators of a physiological as well as a pathological process or pharmacological response to a therapeutic intervention.Classical biomarkers are measurable alterations in blood pressure and blood glucose in diabetes mellitus.And the emerging biomarkers refer to any specific molecular alteration of a cell on DNA,RNA,protein or metabolite levels.In the era of molecular biology,biomarkers usually indicate molecular biomarkers.Biomarkers and molecular diagnostics are inseparable.On the one hand,we can use molecular diagnostic technology to discover biomarkers;on the other hand,biomarkers can be used as the basis of molecular diagnostic tests.With the rapid and robust developmnet of high throughput and high sensitivity technology such as next-generation sequencing technology,chromatography coupled with mass spectrometry technology,biochip and etc,a huge number of data about biomarkers in schizophrenia emerge.Yet,to date,there has not been one biomarker or a panel of biomarkers successfully applied in clinical diagnostics of schizophrenia.Therefore,this doctoral dissertation has intended to targetedly screen potential bloodbased diagnostic biomarkers in schizophrenia based on the published studies.Firstly,we read articles about genetics,transcriptomics,proteomics and metabolomics research on schizophrenia.And then,combined with our research basis and background,we focus on the relationship between the extended major histocompatibility complex(x MHC)region,the 14-3-3 protein family,the fibroblast growth factor 21(FGF21)and schizophrenia.In the principle of "bold assumptions and careful verifications",we have investigated the gene and/or protein expression of the x MHC region,the 14-3-3 family and FGF21 by flexible utilization of different detection platforms and techniques.As a result,we have discovered that there are distinctive gene expression patterns of the x MHC region and unique gene and protein expression patterns of the 14-3-3 protein family in peripheral blood leukocytes of patients with schizophrenia;metabolic regulator FGF21 levels are significantly elevated in schizophrenia;and that two logsitic regression models constructed by fitting a combination of 6 genes in x MHC region and 7 members of the 14-3-3 protein family,respectively,have made very good diagnostic efficacy.Specifically,(1)the area under receiver operating characteristic(ROC)curve(AUC)value is 1,from the logsitic regression model constructed by fitting a combination of 6 genes in x MHC region in the discovery set,which represents an excellent classifier,and in the validation set,AUC=0.8161,sensitivity=0.8108,specifity=0.8537,which also mean good diagnostic efficacy;(2)in the logsitic regression model constructed by fitting a combination of 7 genes in the 14-3-3 protein family in the discovery set,the AUC value is 0.9745,the sensitivity value is 1,and the specifity value is 0.8571,which also shows good diagnostic validity,but the model's performance is not so good in the validation set as that in the discovery set,becuase the value of AUC is just 0.79.Nevertheless,we still expect its diagnostic performance in larger sample sets.For FGF21,its diagnostic performance is truly poor,so we suggest that it can construct the diagnostic model by combining with other cytokines or proteins in sera in the future,so as to show better performance.The results of this study have indicated that the two groups of diagnostic models have very good diagnostic efficacy,and in the future,we will evaluate the diagnostic efficacy of these two group models in larger populations,in order to screen the biomarkers which can be tested in clinical testing phase as the molecular diagnostic test methods.This study provides new ideas and targets for the biomarker studies of schizophrenia and the diagnosis and treatment of the disease,contributes to delving into the pathogenesis of schizophrenia,and supports the personalized treatment as well as the research and development of antipsychotic drugs.