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Gene expression data analysis using Hellinger correlation in weighted gene co-expression networks (WGCNA).

ABSTRACT: Weighted gene co-expression network analysis (WGCNA) is used to detect clusters with highly correlated genes. Measurements of correlation most typically rely on linear relationships. However, a linear relationship does not always model pairwise functional-related dependence between genes. In this paper, we first compared 6 different correlation methods in their ability to capture complex dependence between genes in three different tissues. Next, we compared their gene-pairwise coefficient results and corresponding WGCNA results. Finally, we applied a recently proposed correlation method, Hellinger correlation, as a more sensitive correlation measurement in WGCNA. To test this method, we constructed gene networks containing co-expression gene modules from RNA-seq data of human frontal cortex from Alzheimer's disease patients. To test the generality, we also used a microarray data set from human frontal cortex, single cell RNA-seq data from human prefrontal cortex, RNA-seq data from human temporal cortex, and GTEx data from heart. The Hellinger correlation method captures essentially similar results as other linear correlations in WGCNA, but provides additional new functional relationships as exemplified by uncovering a link between inflammation and mitochondria function. We validated the network constructed with the microarray and single cell sequencing data sets and a RNA-seq dataset of temporal cortex. We observed that this new correlation method enables the detection of non-linear biologically meaningful relationships among genes robustly and provides a complementary new approach to WGCNA. Thus, the application of Hellinger correlation to WGCNA provides a more flexible correlation approach to modelling networks in gene expression analysis that uncovers novel network relationships.

SUBMITTER: Zhang T

PROVIDER: S-EPMC9307959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND Many patients are not responsive or tolerant to medical therapies for carotid atherosclerosis. Thus, elucidating the molecular mechanism for the pathogenesis and progression of carotid atherosclerosis and identifying new potential molecular targets for medical therapies that can slow progression of carotid atherosclerosis and prevent ischemic events are quite important. MATERIAL AND METHODS We downloaded the expression profiling data of PBMC in Biobank of Karolinska Endarterectomy (BiKE, GSE21545) for GEO. The WGCNA and DEG screening were conducted. The co-expression pattern between patients with ischemic events (the events group) and patients without ischemic events (the no-events group) were compared. Then, we identified hub genes of each module. Finally, the DEG co-expression network was constructed and MCODE was used to identify crucial genes based on this co-expression network. RESULTS In the study, 183 DEGs were screened and 8 and 6 modules were assessed in the events group and no-events group, respectively. Compared to the no-events group, genes associated with inflammation and immune response were clustered in the green-yellow module of the events group. The hub gene of the green-yellow module of the events group was KIR2DL5A. We obtained 1 DEG co-expression network, which has 16 nodes and 24 edges, and we detected 5 crucial genes: SIRT1, THRAP3, RBM43, PEX1, and KLHDC2. The upregulated genes (THRAP3 and RBM43) showed potential diagnostic and prognostic value for the occurrence of ischemic events. CONCLUSIONS We detected 8 modules for the events group and 6 modules for the no-events group. The hub genes for modules and crucial genes of the DEG co-expression network were also identified. These genes might serve as potential targets for medical therapies and biomarkers for diagnosis and prognosis. Further experimental and biological studies are needed to elucidate the role of these crucial genes in the progression of carotid atherosclerosis.

Project description:The application of complex network modeling to analyze large co-expression data sets has gained traction during the last decade. In particular, the use of the weighted gene co-expression network analysis framework has allowed an unbiased and systems-level investigation of genotype-phenotype relationships in a wide range of systems. Since mouse is an important model organism for biomedical research on human disease, it is of great interest to identify similarities and differences in the functional roles of human and mouse orthologous genes. Here, we develop a novel network comparison approach which we demonstrate by comparing two gene-expression data sets from a large number of human and mouse tissues. The method uses weighted topological overlap alongside the recently developed network-decomposition method of s-core analysis, which is suitable for making gene-centrality rankings for weighted networks. The aim is to identify globally central genes separately in the human and mouse networks. By comparing the ranked gene lists, we identify genes that display conserved or diverged centrality-characteristics across the networks. This framework only assumes a single threshold value that is chosen from a statistical analysis, and it may be applied to arbitrary network structures and edge-weight distributions, also outside the context of biology. When conducting the comparative network analysis, both within and across the two species, we find a clear pattern of enrichment of transcription factors, for the homeobox domain in particular, among the globally central genes. We also perform gene-ontology term enrichment analysis and look at disease-related genes for the separate networks as well as the network comparisons. We find that gene ontology terms related to regulation and development are generally enriched across the networks. In particular, the genes FOXE3, RHO, RUNX2, ALX3 and RARA, which are disease genes in either human or mouse, are on the top-10 list of globally central genes in the human and mouse networks.

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Gene expression data analysis using Hellinger correlation in weighted gene co-expression networks (WGCNA).

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