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Exploring Potential Biomarkers Underlying Pathogenesis of Alzheimer's Disease by Differential Co-expression Analysis.

ABSTRACT: Background:Alzheimer's Disease (AD) is the most common form of dementia in the elderly. Due to the facts that biological causes of AD are complex in addition to increasing rates of AD worldwide, a deeper understanding of AD etiology is required for AD treatment and diagnosis. Methods:To identify molecular pathological alterations in AD brains, GSE36980 series containing microarray data samples from temporal cortex, frontal cortex and hippocampus were downloaded from Gene Expression Omnibus (GEO) database and valid gene symbols were subjected to building a gene co-expression network by a bioinformatics tool known as differential regulation from differential co-expression (DCGL) software package. Then, a network-driven integrative analysis was performed to find significant genes and underlying biological terms. Results:A total of 17088 unique genes were parsed into three independent differential co-expression networks. As a result, a small number of differentially co-regulated genes mostly in frontal and hippocampus lobs were detected as potential biomarkers related to AD brains. Ultimately differentially co-regulated genes were enriched in biological terms including response to lipid and fatty acid and pathways mainly signaling pathway such as G-protein signaling pathway and glutamate receptor groups II and III. By conducting co-expression analysis, our study identified multiple genes that may play an important role in the pathogenesis of AD. Conclusion:The study aimed to provide a systematic understanding of the potential relationships among these genes and it is hoped that it could aid in AD biomarker discovery.

SUBMITTER: Izadi F

PROVIDER: S-EPMC6252023 | biostudies-other | 2018 Oct-Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundAlzheimer's disease (AD) is one of the leading causes of death in the US and there is no validated drugs to stop, slow or prevent AD. Despite tremendous effort on biomarker discovery, existing findings are mostly individual biomarkers and provide limited insights into the transcriptomic decoupling underlying AD. We propose to explore the gene co-expression patterns in multiple AD stages, including cognitively normal (CN), early mild cognitive impairment (EMCI), late MCI and AD.MethodsWe modified traiditonal joint graphical lasso to model our asusmption that the co-expression networks in consecutive disease stages are largely similar with critical differences. In addition, we performed subsequent network comparison analysis for identification of stage specific transcriptomic decoupling. We focused our analysis on top AD-enriched pathways.ResultsWe observed that 419 edges in CN, 420 edges in EMCI, 381 edges in LMCI and 250 edges in AD were frequently estimated with non zero weights. With modified JGL, the weight of all estimated edges in CN, EMCI and LMCI are zero. In AD group, 299 edges were occasionally estimated to be nonzero and the average correlation between genes was 0.0023. For co-expression change during AD progression, there are 66 pairs of genes that demonstrated a continuously decreasing or increasing co-expression from CN to EMCI, LMCI and AD.The network level clustering coefficient remains stable from CN to LMCI and then decreases significantly when progressing to AD. When evaluating edge level differences, we identified eight gene modules with continuously decreasing or increasing co-expression patterns during AD progression. Five of them shows significant changes from CN to EMCI and thus have the potential to serve system biomarkers for early screening of AD.ConclusionWe employed a modified joint graphical lasso for estimation of co-expression networks for multiple stages of AD. Comparing with graphical lasso, our modified joint graphical lasso model accounts for the similarity in consecutive disease stages. Our results on real data set revealed five gene clusters with obvious co-expression pattern change from CN to EMCI, which could be used as potential system-level biomarkers for early screening of AD.

Project description:BackgroundGlioblastoma (GBM) is the most common malignant tumor in the central system with a poor prognosis. Due to the complexity of its molecular mechanism, the recurrence rate and mortality rate of GBM patients are still high. Therefore, there is an urgent need to screen GBM biomarkers to prove the therapeutic effect and improve the prognosis.ResultsWe extracted data from GBM patients from the Gene Expression Integration Database (GEO), analyzed differentially expressed genes in GEO and identified key modules by weighted gene co-expression network analysis (WGCNA). GSE145128 data was obtained from the GEO database, and the darkturquoise module was determined to be the most relevant to the GBM prognosis by WGCNA (r = - 0.62, p = 0.01). We performed enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to reveal the interaction activity in the selected modules. Then Kaplan-Meier survival curve analysis was used to extract genes closely related to GBM prognosis. We used Kaplan-Meier survival curves to analyze the 139 genes in the darkturquoise module, identified four genes (DARS/GDI2/P4HA2/TRUB1) associated with prognostic GBM. Low expression of DARS/GDI2/TRUB1 and high expression of P4HA2 had a poor prognosis. Finally, we used tumor genome map (TCGA) data, verified the characteristics of hub genes through Co-expression analysis, Drug sensitivity analysis, TIMER database analysis and GSVA analysis. We downloaded the data of GBM from the TCGA database, the results of co-expression analysis showed that DARS/GDI2/P4HA2/TRUB1 could regulate the development of GBM by affecting genes such as CDC73/CDC123/B4GALT1/CUL2. Drug sensitivity analysis showed that genes are involved in many classic Cancer-related pathways including TSC/mTOR, RAS/MAPK.TIMER database analysis showed DARS expression is positively correlated with tumor purity (cor = 0.125, p = 1.07e-02)), P4HA2 expression is negatively correlated with tumor purity (cor =-0.279, p = 6.06e-09). Finally, GSVA analysis found that DARS/GDI2/P4HA2/TRUB1 gene sets are closely related to the occurrence of cancer.ConclusionWe used two public databases to identify four valuable biomarkers for GBM prognosis, namely DARS/GDI2/P4HA2/TRUB1, which have potential clinical application value and can be used as prognostic markers for GBM.

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Exploring Potential Biomarkers Underlying Pathogenesis of Alzheimer's Disease by Differential Co-expression Analysis.

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