Molecular signatures of preeclampsia subtypes determined through integrated weighted gene co-expression network analysis and differential gene expression analysis of placental transcriptomics.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40823529", "kind": "science-record", "revision": 4, "content_hash": "sha256:d0ac83b0385970a422f5be54ada268318907bf241b7ad682183bf5da903c0a96", "created_at": "2026-11-01T20:30:55Z", "updated_at": "2026-11-01T22:57:02Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Molecular signatures of preeclampsia subtypes determined through integrated weighted gene co-expression network analysis and differential gene expression analysis of placental transcriptomics.", "doi": "10.3389/fcell.2025.1635878", "pmid": "40823529", "authors": ["Luhao Han", "Fabricio da Silva Costa", "Anthony Perkins", "Olivia Holland"], "journal": "Frontiers in cell and developmental biology", "year": 2025, "abstract": "Background: Preeclampsia (PE) is a multisystemic pregnancy syndrome that presents in different clinical subtypes. While placental dysfunction is a critical feature of PE, its contribution to different PE subtypes remains unclear. This study aims to use integrated bioinformatics analysis of placental transcriptomics to investigate subtype-specific molecular mechanisms associated with PE.\nMethods: A systematic search of the Gene Expression Omnibus (GEO) repository identified two datasets (GSE234729, n = 123; GSE75010, n = 157) for integrated Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis. We constructed co-expression networks and identified gene modules correlated with three PE subtypes (severe, early-onset and late-onset). Differential gene expression analysis was conducted using the \"limma\" R package. Differentially expressed genes (DEGs) overlapping with PE subtype-correlated WGCNA modules underwent Gene Ontology (GO) enrichment analysis. Consistently dysregulated genes were validated in an additional external dataset (GSE25906) and RT-PCR analysis of placental samples from 21 PE cases and 21 uncomplicated controls.\nResults: We identified distinct molecular signatures associated with each PE subtype. The green gene module was positively correlated with severe PE (r = 0.63, p = 4e-15), containing 179 DEGs primarily involved in lipid metabolism and hypoxia response processes. Early-onset PE had two highly significant gene modules: the yellow module (r = 0.73, p = 4e-15) with 112 DEGs enriched in biological processes related to gonadotrophin secretion and lipid storage, and the black module (r = -0.55, p = 5e-08) with 47 DEGs significantly enriched in chronic inflammation responses. Late-onset PE showed moderate correlation with the ivory module (r = 0.46, p = 5e-05), containing 23 DEGs enriched in p38MAPK stress-response signalling. Cross-subtype analysis identified 20 consistently dysregulated genes across three PE subtypes, with four upregulated genes (LEP, FSTL3, HTRA4, and HK2) confirmed in the external dataset GSE25906. However, RT-PCR validation showed only moderate upregulation without statistical significance.\nConclusion: Though placental dysfunction occurs across all subtypes with a core set of upregulated genes, variation exits in placental gene expression patterns among PE subtypes. Severe and early-onset PE exhibit large molecular perturbations, while late-onset PE presents more subtle alterations. Aberrant placental lipid storage may contribute to disease severity and early manifestation.", "claims": [{"id": "claim-method", "statement": "Differential expression analysis between PE cases and uncomplicated controls was performed using the “limma” R package (Ritchie et al., 2015).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40823529", "locator": "sections[6] \"2.4 Differential expression analysis\" paragraph 2", "quote": "Differential expression analysis between PE cases and uncomplicated controls was performed using the “limma” R package (Ritchie et al., 2015)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40823529", "locator": "sections[20] \"Data availability statement\" paragraph 2", "quote": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Integrated WGCNA and limma differential expression analysis of placental transcriptomic data identified distinct molecular signatures for severe, early-onset, and late-onset preeclampsia.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40823529", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "We identified distinct molecular signatures associated with each PE subtype."}, {"asset": "source:pmid:40823529", "locator": "sections[15] \"3.3.1 Identification of differentially expressed genes\" paragraph 2", "quote": "We performed differential expression analysis for each dataset using criteria (|log2FC| > 0.5, FDR <0.05)."}, {"asset": "source:pmid:40823529", "locator": "sections[15] \"3.3.1 Identification of differentially expressed genes\" paragraph 2", "quote": "In GSE234729 dataset, we identified 953 differentially expressed genes (DEGs) in severe PE, including 457 upregulated genes and 496 downregulated genes."}, {"asset": "source:pmid:40823529", "locator": "sections[15] \"3.3.1 Identification of differentially expressed genes\" paragraph 2", "quote": "Analysis of the GSE75010 dataset revealed 175 DEGs in early-onset PE (103 upregulated and 72 downregulated genes) and 34 DEGs in late-onset PE (26 upregulated and 8 downregulated genes)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Integrated WGCNA and limma differential expression analysis of placental transcriptomic data identified distinct molecular signatures for severe, early-onset, and late-onset preeclampsia.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40823529"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE234729"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE234729"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:40823529", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fcell.2025.1635878", "sha256": "sha256:127e955e01be8d7f8914d4c66c3a709cfb45cf47b7975560705b7841d401062a", "bytes": 60316, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fcell.2025.1635878", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12350358", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE234729", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE234729", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE234729", "version": null, "note": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM7473865", "GSM7473866", "GSM7473867", "GSM7473868", "GSM7473869", "GSM7473870", "GSM7473871", "GSM7473872", "GSM7473873", "GSM7473874", "GSM7473875", "GSM7473876", "GSM7473877", "GSM7473878", "GSM7473879", "GSM7473880", "GSM7473881", "GSM7473882", "GSM7473883", "GSM7473884", "GSM7473885", "GSM7473886", "GSM7473887", "GSM7473888", "GSM7473889", "GSM7473890", "GSM7473891", "GSM7473892", "GSM7473893", "GSM7473894", "GSM7473895", "GSM7473896", "GSM7473897", "GSM7473898", "GSM7473899", "GSM7473900", "GSM7473901", "GSM7473902", "GSM7473903", "GSM7473904", "GSM7473905", "GSM7473906", "GSM7473907", "GSM7473908", "GSM7473909", "GSM7473910", "GSM7473911", "GSM7473912", "GSM7473913", "GSM7473914", "GSM7473915", "GSM7473916", "GSM7473917", "GSM7473918", "GSM7473919", "GSM7473920", "GSM7473921", "GSM7473922", "GSM7473923", "GSM7473924", "GSM7473925", "GSM7473926", "GSM7473927", "GSM7473928", "GSM7473929", "GSM7473930", "GSM7473931", "GSM7473932", "GSM7473933", "GSM7473934", "GSM7473935", "GSM7473936", "GSM7473937", "GSM7473938", "GSM7473939", "GSM7473940", "GSM7473941", "GSM7473942", "GSM7473943", "GSM7473944", "GSM7473945", "GSM7473946", "GSM7473947", "GSM7473948", "GSM7473949", "GSM7473950", "GSM7473951", "GSM7473952", "GSM7473953", "GSM7473954", "GSM7473955", "GSM7473956", "GSM7473957", "GSM7473958", "GSM7473959", "GSM7473960", "GSM7473961", "GSM7473962", "GSM7473963", "GSM7473964", "GSM7478643", "GSM7478644", "GSM7478645", "GSM7478647", "GSM7478648", "GSM7478649", "GSM7478650", "GSM7478651", "GSM7478653", "GSM7478654", "GSM7478655"], "sample_count": 111, "group_sizes": null, "group_sizes_basis": null, "platform": "24676", "taxon": "Homo sapiens", "title": "RNA sequencing identifies human placentalIL3RAas a potential predictor of adverse cardiovascular outcomes in patients with severe preeclampsia", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE25906", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE25906", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE25906", "version": null, "note": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM635904", "GSM635905", "GSM635906", "GSM635907", "GSM635908", "GSM635909", "GSM635910", "GSM635911", "GSM635912", "GSM635913", "GSM635914", "GSM635915", "GSM635916", "GSM635917", "GSM635918", "GSM635919", "GSM635920", "GSM635921", "GSM635922", "GSM635923", "GSM635924", "GSM635925", "GSM635926", "GSM635927", "GSM635928", "GSM635929", "GSM635930", "GSM635931", "GSM635932", "GSM635933", "GSM635934", "GSM635935", "GSM635936", "GSM635937", "GSM635938", "GSM635939", "GSM635940", "GSM635941", "GSM635942", "GSM635943", "GSM635944", "GSM635945", "GSM635946", "GSM635947", "GSM635948", "GSM635949", "GSM635950", "GSM635951", "GSM635952", "GSM635953", "GSM635954", "GSM635955", "GSM635956", "GSM635957", "GSM635958", "GSM635959", "GSM635960", "GSM635961", "GSM635962", "GSM635963"], "sample_count": 60, "group_sizes": null, "group_sizes_basis": null, "platform": "6102", "taxon": "Homo sapiens", "title": "Transcriptional Profiling of Human Placentas from Pregnancies Complicated by Preeclampsia Reveals Disregulation of Sialic Acid Acetylesterase and Immune Signaling Pathways", "resolution_checked_at": "2026-11-01T19:09:46Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE75010", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE75010", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE75010", "version": null, "note": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1940492", "GSM1940493", "GSM1940494", "GSM1940495", "GSM1940496", "GSM1940497", "GSM1940498", "GSM1940499", "GSM1940500", "GSM1940501", "GSM1940502", "GSM1940503", "GSM1940504", "GSM1940505", "GSM1940506", "GSM1940507", "GSM1940508", "GSM1940509", "GSM1940510", "GSM1940511", "GSM1940512", "GSM1940513", "GSM1940514", "GSM1940515", "GSM1940516", "GSM1940517", "GSM1940518", "GSM1940519", "GSM1940520", "GSM1940521", "GSM1940522", "GSM1940523", "GSM1940524", "GSM1940525", "GSM1940526", "GSM1940527", "GSM1940528", "GSM1940529", "GSM1940530", "GSM1940531", "GSM1940532", "GSM1940533", "GSM1940534", "GSM1940535", "GSM1940536", "GSM1940537", "GSM1940538", "GSM1940539", "GSM1940540", "GSM1940541", "GSM1940542", "GSM1940543", "GSM1940544", "GSM1940545", "GSM1940546", "GSM1940547", "GSM1940548", "GSM1940549", "GSM1940550", "GSM1940551", "GSM1940552", "GSM1940553", "GSM1940554", "GSM1940555", "GSM1940556", "GSM1940557", "GSM1940558", "GSM1940559", "GSM1940560", "GSM1940561", "GSM1940562", "GSM1940563", "GSM1940564", "GSM1940565", "GSM1940566", "GSM1940567", "GSM1940568", "GSM1940569", "GSM1940570", "GSM1940571", "GSM1940572", "GSM1940573", "GSM1940574", "GSM1940575", "GSM1940576", "GSM1940577", "GSM1940578", "GSM1940579", "GSM1940580", "GSM1940581", "GSM1940582", "GSM1940583", "GSM1940584", "GSM1940585", "GSM1940586", "GSM1940587", "GSM1940588", "GSM1940589", "GSM1940590", "GSM1940591", "GSM1940592", "GSM1940593", "GSM1940594", "GSM1940595", "GSM1940596", "GSM1940597", "GSM1940598", "GSM1940599", "GSM1940600", "GSM1940601", "GSM1940602", "GSM1940603", "GSM1940604", "GSM1940605", "GSM1940606", "GSM1940607", "GSM1940608", "GSM1940609", "GSM1940610", "GSM1940611", "GSM1940612", "GSM1940613", "GSM1940614", "GSM1940615", "GSM1940616", "GSM1940617", "GSM1940618", "GSM1940619", "GSM1940620", "GSM1940621", "GSM1940622", "GSM1940623", "GSM1940624", "GSM1940625", "GSM1940626", "GSM1940627", "GSM1940628", "GSM1940629", "GSM1940630", "GSM1940631", "GSM1940632", "GSM1940633", "GSM1940634", "GSM1940635", "GSM1940636", "GSM1940637", "GSM1940638", "GSM1940639", "GSM1940640", "GSM1940641", "GSM1940642", "GSM1940643", "GSM1940644", "GSM1940645", "GSM1940646", "GSM1940647", "GSM1940648"], "sample_count": 157, "group_sizes": null, "group_sizes_basis": null, "platform": "6244", "taxon": "Homo sapiens", "title": "Placental gene expression profiling for the identification of clinically relevant subclasses of human preeclampsia", "resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE234729 not downloaded", "asset:data:geo:GSE234729 licence not read", "asset:data:geo:GSE25906 not downloaded", "asset:data:geo:GSE25906 licence not read", "asset:data:geo:GSE75010 not downloaded", "asset:data:geo:GSE75010 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "differential_expression", "specific": "limma_voom", "label": "Differential expression analysis", "dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["count_matrix_with_condition"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "Differential expression analysis between PE cases and uncomplicated controls was performed using the “limma” R package (Ritchie et al., 2015)."}}], "targets": [], "gaps": []}, "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": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: limma_voom."}, "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": ["GSE234729", "GSE75010", "GSE25906"], "resolved_accessions": ["GSE234729", "GSE75010", "GSE25906"], "statements": ["The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author."], "basis": "The paper names GSE234729, GSE75010, GSE25906 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": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "assets": ["source:pmid:40823529", "data:geo:GSE234729"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE234729"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:59:41Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 16715, "completion_tokens": 1418, "cached_tokens": 256}}, "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:40823529", "type": "paper", "label": "pmid:40823529"}, {"id": "source:pmid:40823529", "type": "manuscript", "label": "PMID 40823529 full text"}, {"id": "data:geo:GSE234729", "type": "dataset", "label": "GEO GSE234729"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40823529", "type": "paper", "label": "pmid:40823529"}, {"id": "source:pmid:40823529", "type": "manuscript", "label": "PMID 40823529 full text"}, {"id": "data:geo:GSE234729", "type": "dataset", "label": "GEO GSE234729"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40823529", "type": "extraction", "used": ["source:pmid:40823529"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE234729", "type": "accession_resolution", "used": ["data:geo:GSE234729"], "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:40823529", "parent_hash": "sha256:eb4a8ceae8cb68294e6d273d08a3c6177440f190cf2a619a3a2d002c627a4d2d", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE234729 licence not read", "asset:data:geo:GSE234729 not downloaded", "asset:data:geo:GSE25906 licence not read", "asset:data:geo:GSE25906 not downloaded", "asset:data:geo:GSE75010 licence not read", "asset:data:geo:GSE75010 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ression was quantified via quantitative PCR (qPCR) using SYBR Green Mix (Qiagen) with gene-spe"], "order_basis": "paper_text_order:4096", "id": "assay:1"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Differential expression analysis between PE cases and uncomplicated controls was performed using the “limma” R package (Ritchie et al., 2015)."], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}