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pmid:34522169
Identification of Key Genes and Pathways associated with Endometriosis by Weighted Gene Co-expression Network Analysis.
Jingni Wu · Xiaoling Fang · Xiaomeng Xia
International journal of medical sciences · 2021 doi:10.7150/ijms.63541
Paper
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Experiment
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Complete file
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This study aimed to elucidate potential hub genes and key pathways associated with endometriosis in ectopic endometrium (EC) and eutopic endometrium (EU). Material and Method: EC and EU-associated microarray datasets were obtained from the gene expression omnibus (GEO) database. Gene set enrichment analysis was performed to obtain further biological insight into the EU and EC-associated genes. Weighted gene co-expression network analysis (WGCNA) was performed to find clinically significant modules of highly-correlated genes. The hub genes that belong to both the weighted gene co-expression network and protein-protein interaction (PPI) network were identified using a Venn diagram. Results: We obtained EC and EU-associated microarray datasets GSE7305 and GSE120103. Genes in the EC were mainly enriched in the immune response and immune cell trafficking, and genes in the EU were mainly enriched in stress response and steroid hormone biosynthesis. PPI networks and weighted gene co-expression networks were constructed. An EC-associated blue module and an EU-associated magenta module were identified, and their function annotations revealed that hormone receptor signaling or inflammatory microenvironments may promote EU passing through the oviducts and migrating to the ovarian surfaces, and adhesion and immune correlated genes may induce the successful ectopic implantation of the endometrium (EC). Twelve hub genes in the EC and sixteen hub genes in the EU were recognized and further validated in independent datasets. 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"note": "The GO and KEGG Pathway analysis of genes in the magenta module", "structure": {"pmcid": "PMC8436105", "section_index": 16, "section_title": "Function analysis of the most significant module", "row_count": 30, "column_count": 4}, "table": {"label": "Table 2", "caption": "The GO and KEGG Pathway analysis of genes in the magenta module", "rows": [["Category", "Term", "Description", "Log(p-value)"], ["GO Biological Processes", "GO:0043408", "regulation of MAPK cascade", "-6.05131099"], ["GO Biological Processes", "GO:0043409", "negative regulation of MAPK cascade", "-4.84419894"], ["GO Biological Processes", "GO:1903351", "cellular response to dopamine", "-4.25433626"], ["GO Biological Processes", "GO:0035666", "TRIF-dependent toll-like receptor signaling pathway", "-3.72907579"], ["GO Biological Processes", "GO:0060398", "regulation of growth hormone receptor signaling pathway", "-3.59181535"], ["GO Biological Processes", "GO:1904407", "positive regulation of nitric oxide 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"locator": "section[16]/table-wrap[2]#T2"}}, {"id": "asset:table:pmid:34522169:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:82cd5f460615a905a8644007fc40ef4d09165331fdff1e939cb89ad15a0cdc6d", "bytes": 4128, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[17]/table-wrap[1]#T3", "version": null, "note": "The common hub genes of WGCNA and PPI analysis in the blue and magenta modules", "structure": {"pmcid": "PMC8436105", "section_index": 17, "section_title": "Identification of hub genes", "row_count": 30, "column_count": 11}, "table": {"label": "Table 3", "caption": "The common hub genes of WGCNA and PPI analysis in the blue and magenta modules", "rows": [["Gene Symbol", "Gene Description", "Module", "WGCNA", "PPI Analysis", "Limma Analysis"], ["GS", "GS P value", "MM", "MM, P value", "K Score", "Log2FC", "FDR", "Up or Down"], ["ACTG2", "actin, gamma 2, smooth muscle, enteric", "blue", "0.922139646", "7.51E-09", "0.923366176", "6.54E-09", "5.667", "3.548158459", "1.02E-08", "up"], ["C1R", "complement C1r subcomponent", "blue", "0.897984733", "7.81E-08", "0.96174151", "1.45E-11", "4", "2.208552292", "1.14E-07", "up"], ["CDH3", "cadherin 3", "blue", "0.931420936", "2.48E-09", "0.971836642", "9.56E-13", "6.2", "2.775338929", "3.97E-09", "up"], ["CLU", "clusterin", "blue", "0.863575842", "9.38E-07", "0.878310934", "3.54E-07", "4", "2.044619742", "1.29E-06", "up"], ["COL8A1", "collagen type VIII alpha 1 chain", "blue", "0.92193141", "7.69E-09", "0.941172973", "6.47E-10", "3", "4.329881143", "1.01E-08", "Up"], ["GATA6", "GATA binding protein 6", "blue", "0.98763453", "6.14E-16", "0.972736196", "7.16E-13", "5.667", "4.878194698", "1.42E-15", "up"], ["HOXC6", "homeobox C6", "blue", "0.944317318", "3.99E-10", "0.90875176", "2.98E-08", "4.8", "3.487499137", "6.36E-10", "up"], ["LMOD1", "leiomodin 1", "blue", "0.880126801", "3.12E-07", "0.947799849", "2.26E-10", "5.667", "2.476035697", "4.14E-07", "up"], ["MYH11", "myosin heavy chain 11", "blue", "0.933072838", "2.00E-09", "0.975751992", "2.52E-13", "5.667", "3.708376486", "2.96E-09", "Up"], ["MYLK", "myosin light chain kinase", "blue", "0.914954646", "1.62E-08", "0.94723591", "2.48E-10", "5.667", "2.125367821", "2.54E-08", "up"], ["MYOCD", "myocardin", "blue", "0.859995861", "1.17E-06", "0.929712545", "3.08E-09", "5.667", "3.441041169", "1.43E-06", "up"], ["PROS1", "protein S (alpha)", "blue", "0.934607399", "1.64E-09", "0.984275338", "5.27E-15", "4", "2.899254277", "2.67E-09", "up"], ["SERPING1", "serpin family G member 1", "blue", "0.859067114", "1.23E-06", "0.937390849", "1.12E-09", "4", "2.424791429", "1.61E-06", "up"], ["TAGLN", "transgelin", "blue", "0.909061849", "2.89E-08", "0.959903156", "2.20E-11", "5.667", "2.815676431", "3.97E-08", "up"], ["THBS1", "thrombospondin 1", "blue", "0.764480323", "8.68E-05", "0.84490284", "2.77E-06", "4", "2.047575043", "0.000118406", "up"], ["THBS2", "thrombospondin 2", "blue", "0.870101501", "6.18E-07", "0.92128971", "8.25E-09", "3", "2.397111323", "8.17E-07", "up"], ["ABCC8", "ATP binding cassette subfamily C member 8", "magenta", "0.726050115", "0.000966995", "0.922624053", "1.35214E-07", "3", "2.368106299", "0.000000474", "Up"], ["COL4A6", "collagen type IV alpha 6 chain", "magenta", "0.831303264", "3.54879E-05", "0.873736048", "4.59798E-06", "4.71", "3.592049292", "5.82E-08", "up"], ["COL5A3", "collagen type V alpha 3 chain", "magenta", "0.864722139", "7.50448E-06", "0.96496314", "4.02139E-10", "4.71", "2.690812909", "6.65E-08", "up"], ["CXCL13", "C-X-C motif chemokine ligand 13", "magenta", "0.676038594", "2.89E-03", "0.808787134", "8.47082E-05", "20.9", "2.692421845", "0.00000669", "up"], ["CYP2E1", "cytochrome P450 family 2 subfamily E member 1", "magenta", "0.813393515", "7.1566E-05", "0.937472578", "2.85784E-08", "4.5", "2.3219305", "4.78E-08", "up"], ["CYP4B1", "cytochrome P450 family 4 subfamily B member 1", "magenta", "0.736111943", "0.000754364", "0.858320627", "1.04106E-05", "4.5", "3.0752333", "0.000000839", "up"], ["DKK1", "dickkopf WNT signaling pathway inhibitor 1", "magenta", "0.697058489", "0.001871854", "0.815860925", "6.53E-05", "4.71", "3.533265993", "0.000000546", "up"], ["FSTL3", "follistatin like 3", "magenta", "0.76382863", "0.000358509", "0.894831724", "1.24E-06", "5.067", "2.997977144", "0.000000244", "up"], ["KLF4", "Kruppel like factor 4", "magenta", "0.725261009", "0.000985574", "0.884368596", "2.45E-06", "4.71", "3.223838581", "9.88E-08", "up"], ["NR4A2", "nuclear receptor subfamily 4 group A member 2", "magenta", "0.800101777", "0.000115047", "0.864686086", "7.52E-06", "4.71", "3.44866934", "4.88E-08", "up"], ["PROK1", "prokineticin 1", "magenta", "0.830706844", "3.6373E-05", "0.807977649", "8.72E-05", "11", "4.082022638", "1.93E-08", "up"], ["WDR27", "WD repeat domain 27", "magenta", "0.790440633", "0.000159037", "0.950669894", "5.02E-09", "3", "2.232448342", "9.99E-08", "up"]], "row_count": 30, "column_count": 11, "numeric_cells": 220, "header_rows": 2, "locator": "section[17]/table-wrap[1]#T3"}}], "gaps": ["asset:data:geo:GSE120103 not downloaded", "asset:data:geo:GSE120103 licence not read", "asset:data:geo:GSE51981 not downloaded", "asset:data:geo:GSE51981 licence not read", "asset:data:geo:GSE7305 not downloaded", "asset:data:geo:GSE7305 licence not read", "asset:data:geo:GSE7307 not downloaded", "asset:data:geo:GSE7307 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "network_analysis", "specific": "ppi_network", "label": "Network / pathway analysis", "dsl_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.7, "band": "medium", "quote": "protein-protein interaction"}}, {"id": "method-2", "family": null, "specific": null, "label": "Weighted gene co-expression network analysis (WGCNA)", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "reordered", "quote": "\"We used the WGCNA R package to establish co-expression networks 14 for the genes in GSE7305 and GSE120103.\" \"Expression profiles of endometriosis-associated mRNAs in GSE7305, GSE120103, GSE7307 and GSE51981 were downloaded from Gene Expression Omnibus (GEO) database.\""}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: ppi_network."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE7305", "GSE120103", "GSE7307", "GSE51981"], "resolved_accessions": ["GSE7305", "GSE120103", "GSE7307", "GSE51981"], "statements": ["The following publicly-available datasets were analyzed in this study: [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120103]; [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE7305]; [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi]; [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51981]."], "basis": "The paper names GSE7305, GSE120103, GSE7307, GSE51981 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "assets": ["source:pmid:34522169", "data:geo:GSE120103", "asset:table:pmid:34522169:1", "asset:table:pmid:34522169:2", "asset:table:pmid:34522169:3"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE120103"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:34:41Z", "independence": "single_reader"}, "evidence_check": {"method": "reordered", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 26347, "completion_tokens": 1966, "cached_tokens": 784}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:34522169", "type": "paper", "label": "pmid:34522169"}, {"id": "source:pmid:34522169", "type": "manuscript", "label": "PMID 34522169 full text"}, {"id": "data:geo:GSE120103", "type": "dataset", "label": "GEO GSE120103"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34522169", "type": "paper", "label": "pmid:34522169"}, {"id": "source:pmid:34522169", "type": "manuscript", "label": "PMID 34522169 full text"}, {"id": "data:geo:GSE120103", "type": "dataset", "label": "GEO GSE120103"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34522169", "type": "extraction", "used": ["source:pmid:34522169"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE120103", "type": "accession_resolution", "used": ["data:geo:GSE120103"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:34522169", "parent_hash": "sha256:f91e74a7c79fa07942858374b267f0e963dabba331c10c427c9686fed36b884c", "fork_of": null, "generation": 4}, "gaps": ["asset:data:geo:GSE120103 licence not read", "asset:data:geo:GSE120103 not downloaded", "asset:data:geo:GSE51981 licence not read", "asset:data:geo:GSE51981 not downloaded", "asset:data:geo:GSE7305 licence not read", "asset:data:geo:GSE7305 not downloaded", "asset:data:geo:GSE7307 licence not read", "asset:data:geo:GSE7307 not downloaded", "execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["). Material and Method: EC and EU-associated microarray datasets were obtained from the gene express", "m. Results: We obtained EC and EU-associated microarray datasets GSE7305 and GSE120103. Genes in the"], "order_basis": "paper_text_order:449", "id": "assay:1"}, {"role": "analysis", "definition_id": "network_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.7, "evidence": ["protein-protein interaction"], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}