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Identification of diagnostic markers for major depressive disorder by cross-validation of data from whole blood samples.

ABSTRACT: Background:Major depressive disorder (MDD) is a severe disease characterized by multiple pathological changes. However, there are no reliable diagnostic biomarkers for MDD. The aim of the current study was to investigate the gene network and biomarkers underlying the pathophysiology of MDD. Methods:In this study, we conducted a comprehensive analysis of the mRNA expression profile of MDD using data from Gene Expression Omnibus (GEO). The MDD dataset (GSE98793) with 128 MDD and 64 control whole blood samples was divided randomly into two non-overlapping groups for cross-validated differential gene expression analysis. The gene ontology (GO) enrichment and gene set enrichment analysis (GSEA) were performed for annotation, visualization, and integrated discovery. Protein-protein interaction (PPI) network was constructed by STRING database and hub genes were identified by the CytoHubba plugin. The gene expression difference and the functional similarity of hub genes were investigated for further gene expression and function exploration. Moreover, the receiver operating characteristic curve was performed to verify the diagnostic value of the hub genes. Results:We identified 761 differentially expressed genes closely related to MDD. The Venn diagram and GO analyses indicated that changes in MDD are mainly enriched in ribonucleoprotein complex biogenesis, antigen receptor-mediated signaling pathway, catalytic activity (acting on RNA), structural constituent of ribosome, mitochondrial matrix, and mitochondrial protein complex. The GSEA suggested that tumor necrosis factor signaling pathway, Toll-like receptor signaling pathway, apoptosis pathway, and NF-kappa B signaling pathway are all crucial in the development of MDD. A total of 20 hub genes were selected via the PPI network. Additionally, the identified hub genes were downregulated and show high functional similarity and diagnostic value in MDD. Conclusions:Our findings may provide novel insight into the functional characteristics of MDD through integrative analysis of GEO data, and suggest potential biomarkers and therapeutic targets for MDD.

SUBMITTER: Wang H

PROVIDER: S-EPMC6590482 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of diagnostic markers for major depressive disorder by cross-validation of data from whole blood samples.

Wang Huimei H Zhang Mingwei M Xie Qiqi Q Yu Jin J Qi Yan Y Yue Qiuyuan Q

PeerJ 20190621

<h4>Background</h4>Major depressive disorder (MDD) is a severe disease characterized by multiple pathological changes. However, there are no reliable diagnostic biomarkers for MDD. The aim of the current study was to investigate the gene network and biomarkers underlying the pathophysiology of MDD.<h4>Methods</h4>In this study, we conducted a comprehensive analysis of the mRNA expression profile of MDD using data from Gene Expression Omnibus (GEO). The MDD dataset (GSE98793) with 128 MDD and 64 ...[more]

PMID: 31275757

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:BackgroundMajor depressive disorder (MDD) is a global health challenge that impacts the quality of patients' lives severely. The disorder can manifest in many forms with different combinations of symptoms, which makes its clinical diagnosis difficult. Robust biomarkers are greatly needed to improve diagnosis and to understand the etiology of the disease. The main purpose of this study was to create a predictive model for MDD diagnosis based on peripheral blood transcriptomes.Materials and methodsWe collected nine RNA expression datasets for MDD patients and healthy samples from the Gene Expression Omnibus database. After a series of quality control and heterogeneity tests, 302 samples from six studies were deemed suitable for the study. R package "MetaOmics" was applied for systematic meta-analysis of genome-wide expression data. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic effectiveness of individual genes. To obtain a better diagnostic model, we also adopted the support vector machine (SVM), random forest (RF), k-nearest neighbors (kNN), and naive Bayesian (NB) tools for modeling, with the RF method being used for feature selection.ResultsOur analysis revealed six differentially expressed genes (AKR1C3, ARG1, KLRB1, MAFG, TPST1, and WWC3) with a false discovery rate (FDR) < 0.05 between MDD patients and control subjects. We then evaluated the diagnostic ability of these genes individually. With single gene prediction, we achieved a corresponding area under the curve (AUC) value of 0.63 ± 0.04, 0.67 ± 0.07, 0.70 ± 0.11, 0.64 ± 0.08, 0.68 ± 0.07, and 0.62 ± 0.09, respectively, for these genes. Next, we constructed the classifiers of SVM, RF, kNN, and NB with an AUC of 0.84 ± 0.09, 0.81 ± 0.10, 0.73 ± 0.11, and 0.83 ± 0.09, respectively, in validation datasets, suggesting that the SVM classifier might be superior for constructing an MDD diagnostic model. The final SVM classifier including 70 feature genes was capable of distinguishing MDD samples from healthy controls and yielded an AUC of 0.78 in an independent dataset.ConclusionThis study provides new insights into potential biomarkers through meta-analysis of GEO data. Constructing different machine learning models based on these biomarkers could be a valuable approach for diagnosing MDD in clinical practice.

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Identification of diagnostic markers for major depressive disorder by cross-validation of data from whole blood samples.

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Identification of diagnostic markers for major depressive disorder by cross-validation of data from whole blood samples.

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