Dataset Information

Differential gene regulatory pattern in the human brain from schizophrenia using transcriptomic-causal network.

ABSTRACT:

Background

Common and complex traits are the consequence of the interaction and regulation of multiple genes simultaneously, therefore characterizing the interconnectivity of genes is essential to unravel the underlying biological networks. However, the focus of many studies is on the differential expression of individual genes or on co-expression analysis.

Methods

Going beyond analysis of one gene at a time, we systematically integrated transcriptomics, genotypes and Hi-C data to identify interconnectivities among individual genes as a causal network. We utilized different machine learning techniques to extract information from the network and identify differential regulatory pattern between cases and controls. We used data from the Allen Brain Atlas for replication.

Results

Employing the integrative systems approach on the data from CommonMind Consortium showed that gene transcription is controlled by genetic variants proximal to the gene (cis-regulatory factors), and transcribed distal genes (trans-regulatory factors). We identified differential gene regulatory patterns in SCZ-cases versus controls and novel SCZ-associated genes that may play roles in the disorder since some of them are primary expressed in human brain. In addition, we observed genes known associated with SCZ are not likely (OR?=?0.59) to have high impacts (degree?>?3) on the network.

Conclusions

Causal networks could reveal underlying patterns and the role of genes individually and as a group. Establishing principles that govern relationships between genes provides a mechanistic understanding of the dysregulated gene transcription patterns in SCZ and creates more efficient experimental designs for further studies. This information cannot be obtained by studying a single gene at the time.

SUBMITTER: Yazdani A

PROVIDER: S-EPMC7579819 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Differential gene regulatory pattern in the human brain from schizophrenia using transcriptomic-causal network.

Yazdani Akram A Mendez-Giraldez Raul R Yazdani Azam A Kosorok Michael R MR Roussos Panos P

BMC bioinformatics 20201021 1

<h4>Background</h4>Common and complex traits are the consequence of the interaction and regulation of multiple genes simultaneously, therefore characterizing the interconnectivity of genes is essential to unravel the underlying biological networks. However, the focus of many studies is on the differential expression of individual genes or on co-expression analysis.<h4>Methods</h4>Going beyond analysis of one gene at a time, we systematically integrated transcriptomics, genotypes and Hi-C data to ...[more]

PMID: 33087039

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Project description:Biological and medical sciences are increasingly acknowledging the significance of gene co-expression-networks for investigating complex-systems, phenotypes or diseases. Typically, complex phenotypes are investigated under varying conditions. While approaches for comparing nodes and links in two networks exist, almost no methods for the comparison of multiple networks are available and-to best of our knowledge-no comparative method allows for whole transcriptomic network analysis. However, it is the aim of many studies to compare networks of different conditions, for example, tissues, diseases, treatments, time points, or species. Here we present a method for the systematic comparison of an unlimited number of networks, with unlimited number of transcripts: Co-expression Differential Network Analysis (CoDiNA). In particular, CoDiNA detects links and nodes that are common, specific or different among the networks. We developed a statistical framework to normalize between these different categories of common or changed network links and nodes, resulting in a comprehensive network analysis method, more sophisticated than simply comparing the presence or absence of network nodes. Applying CoDiNA to a neurogenesis study we identified candidate genes involved in neuronal differentiation. We experimentally validated one candidate, demonstrating that its overexpression resulted in a significant disturbance in the underlying gene regulatory network of neurogenesis. Using clinical studies, we compared whole transcriptome co-expression networks from individuals with or without HIV and active tuberculosis (TB) and detected signature genes specific to HIV. Furthermore, analyzing multiple cancer transcription factor (TF) networks, we identified common and distinct features for particular cancer types. These CoDiNA applications demonstrate the successful detection of genes associated with specific phenotypes. Moreover, CoDiNA can also be used for comparing other types of undirected networks, for example, metabolic, protein-protein interaction, ecological and psychometric networks. CoDiNA is publicly available as an R package in CRAN (https://CRAN.R-project.org/package=CoDiNA).

Project description:Brain tumor research has been stapled for human health while brain network research is crucial for us to understand brain activity. Here the structural controllability theory is applied to study three human brain-specific gene regulatory networks, including forebrain gene regulatory network, hindbrain gene regulatory network and neuron associated cells cancer related gene regulatory network, whose nodes are neural genes and the edges represent the gene expression regulation among the genes. The nodes are classified into two classes: critical nodes and ordinary nodes, based on the change of the number of driver nodes upon its removal. Eight topological properties (out-degree DO, in-degree DI, degree D, betweenness B, closeness CA, in-closeness CI, out-closeness CO and clustering coefficient CC) are calculated in this paper and the results prove that the critical genes have higher score of topological properties than the ordinary genes. Then two bioinformatic analysis are used to explore the biologic significance of the critical genes. On the one hand, the enrichment scores in several kinds of gene databases are calculated and reveal that the critical nodes are richer in essential genes, cancer genes and the neuron related disease genes than the ordinary nodes, which indicates that the critical nodes may be the biomarker in brain-specific gene regulatory network. On the other hand, GO analysis and KEGG pathway analysis are applied on them and the results show that the critical genes mainly take part in 14 KEGG pathways that are transcriptional misregulation in cancer, pathways in cancer and so on, which indicates that the critical genes are related to the brain tumor. Finally, by deleting the edges or routines in the network, the robustness analysis of node classification is realized, and the robustness of node classification is proved. The comparison of neuron associated cells cancer related GRN (Gene Regulatory Network) and normal brain-specific GRNs (including forebrain and hindbrain GRN) shows that the neuron-related cell cancer-related gene regulatory network is more robust than other types.

Dataset Information

Differential gene regulatory pattern in the human brain from schizophrenia using transcriptomic-causal network.

Background

Methods

Results

Conclusions

Publications

Differential gene regulatory pattern in the human brain from schizophrenia using transcriptomic-causal network.

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