{"doi":"10.3390/ijms262211184","title":"Multimodal Integration of Genomic Data Reveals Regulatory Mechanisms at the Polycystic Ovary Syndrome (PCOS)-Associated 12q13.2 Locus","abstract":"Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting reproductive-aged women. Previous studies have identified genomic associations at chromosome 12q13.2, but the functional mechanisms underlying these associations remain unclear. We integrated three complementary datasets: (1) WES-identified single nucleotide variants (SNVs) from PCOS and normal theca cells with association testing for forskolin-stimulated androgen production, (2) STARR-seq enhancer activity data with eQTL colocalization analysis, and (3) scRNA-seq expression data comparing forskolin-stimulated PCOS and normal theca cells. We previously identified haplotypes involving 10 SNVs at 12q13.2 containing RPS26/RAB5B/SUOX that are significantly associated with forskolin-stimulated androgen production. The identified haplotypes were further shown to associate with PCOS in a whole genome sequencing (WGS) cohort. Other studies have recently found the enhancer variant rs1081975 demonstrated perfect colocalization (PP = 1.0) with RPS26/RAB5B/SUOX eQTLs. Our scRNA-seq analysis revealed differential expression patterns for key genes. RAB5B showed a forskolin response upregulation in normal cells but an impaired response in PCOS. SUOX exhibited opposite forskolin responses between normal and PCOS cells. PA2G4, an androgen corepressor in the locus, was upregulated in normal untreated cells. ERBB3, an epidermal growth factor receptor in the locus, was downregulated in normal forskolin treated cells. The integration of multimodal genomic data provides functional validation of PCOS-associated variants at 12q13.2, revealing coordinated dysregulation of vesicular trafficking (RAB5B), androgen receptor regulation (PA2G4), and metabolic processes (SUOX) in PCOS theca cells.","journal":"International Journal of Molecular Sciences","year":2025,"id":581721,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":0.0,"corpus_rank":10062,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.8815,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":52.0833,"fair_percentile":67.4411494955671,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329123,"name":"Jan M. McAllister","orcid":"0000-0002-6910-2801","position":1,"is_corresponding":false},{"id":301374,"name":"Jerome F. Strauss","orcid":"0000-0001-6199-0480","position":2,"is_corresponding":false},{"id":63735,"name":"R. Alan Harris","orcid":"0000-0002-7333-4752","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41303667","pmcid":"PMC12652976","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":72.2222,"fair_a":81.25,"fair_i":20.0,"fair_r":29.1667,"fair_zscore":0.698,"fair_rationale":{"fair_score":52.08,"has_llm":true,"taxonomy_version":"fair_taxonomy_v5","dimensions":{"F":{"name":"Findable","score":72.22,"criteria":[{"key":"f_dataset_pid","label":"Persistent identifier for the data","kind":"llm","weight":2.0,"fraction":0.5,"verdict":"partial","evidence":"The 10× Cell Ranger filtered feature-barcode matrix data files and the scRNA-seq data are publicly available for download at https://zenodo.org/record/7942968 (accessed on 1 October 2025).","grounded":true,"rationale":"A web address (https://zenodo.org/record/7942968) is given; 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[majority verdict 'yes' (4/5 passes agreed)]","anchors":["RDA-I3-01M — '(meta)data include references to other (meta)data'","RDA-I3-03M — 'metadata includes qualified references to other metadata'","FsF-I3-01M — F-UJI: 'Metadata includes links between the data and its related entities'"],"scored":false,"signal":null}]},"R":{"name":"Reusable","score":29.17,"criteria":[{"key":"r_reuse_license","label":"Reuse licence","kind":"llm","weight":2.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No reuse license or terms document is named for the data; the article is CC BY but that license is for the paper, not the data.","anchors":["RDA-R1.1-01M — 'Metadata includes information about the licence under which the data can be reu","RDA-R1.1-02M — 'Metadata refers to a standard reuse licence'","RDA-R1.1-03M — 'Metadata refers to a machine-understandable reuse licence'"],"scored":true,"signal":null},{"key":"r_provenance_methods","label":"Provenance of the data","kind":"llm","weight":1.0,"fraction":1.0,"verdict":"yes","evidence":"Libraries were sequenced on an Illumina NextSeq 500 to generate 91 bp reads.","grounded":true,"rationale":"The paper names specific instruments and software (Illumina NextSeq 500, Cell Ranger v6.1.1, Seurat v4.1.1, etc.) used to produce the data.","anchors":["RDA-R1.2-01M — 'Metadata includes provenance information according to community- specific standa","FsF-R1.2-01M — F-UJI: 'Metadata includes provenance information about data creation or generati","W3C PROV-O (W3C Recommendation, 2013) — the entity/activity/agent model of provenance"],"scored":false,"signal":null},{"key":"r_documentation_codebook","label":"Documentation / codebook","kind":"llm","weight":1.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No README, data dictionary, or codebook is mentioned as accompanying the deposited data; variable definitions are only inside the article (Table 1).","anchors":["RDA-R1-01M — '(Meta)data are richly described with a plurality of accurate and relevant attribu","FsF-R1-01MD — F-UJI: 'Metadata specifies the content of the data'","NIH DMS Policy Element 3 (NOT-OD-21-014) — Standards (documentation and metadata to accompany t"],"scored":false,"signal":null},{"key":"r_versioning","label":"Snapshot identified","kind":"llm","weight":0.5,"fraction":0.5,"verdict":"partial","evidence":"The 10× Cell Ranger filtered feature-barcode matrix data files and the scRNA-seq data are publicly available for download at https://zenodo.org/record/7942968 (accessed on 1 October 2025).","grounded":true,"rationale":"No version token is given; the access date (1 October 2025) pins the snapshot.","anchors":["DataCite Metadata Schema 4.6 — the 'Version' property","RDA-R1.2-01M — provenance information (which version was used is provenance)","NSTC Desirable Characteristics of Data Repositories (2022) — 'Provenance', 'Retention Policy'"],"scored":true,"signal":null},{"key":"x_code_availability","label":"Analysis code available","kind":"llm","weight":1.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No code locator (repository URL, DOI, or package identifier) is provided; the only offer is not stated.","anchors":["NIH DMS Policy Element 2 (NOT-OD-21-014) — 'Related Tools, Software and/or Code'","FAIR4RS Principles v1.0 (Chue Hong et al., 2022; RDA/FORCE11/ReSA) — FAIR Principles for Resear","FORCE11 Software Citation Principles (Smith, Katz & Niemeyer, 2016, PeerJ CS 2:e86)"],"scored":true,"signal":null},{"key":"x_funding_attribution","label":"Funder and award number","kind":"llm","weight":0.5,"fraction":1.0,"verdict":"yes","evidence":"This research was funded by the National Institutes of Health, grant numbers R01HD083323 (J.M.M. and J.F.S.III) and R01HD033852 (J.M.M.), and a Penn State College of Medicine Bridge Grant (J.M.M).","grounded":true,"rationale":"Award numbers (R01HD083323, R01HD033852) are attached to named funders. 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'Free to use' is not a licence: it grants nothing a reuser's institution can rely on.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No reuse license or terms document is named for the data; the article is CC BY but that license is for the paper, not the data.","gain":16.67,"priority":"essential","scored":true},{"key":"f_dataset_pid","dimension":"F","label":"Persistent identifier for the data","action":"Mint or cite a persistent identifier for the dataset — a repository DOI or an accession from a registered repository — and print it in the paper. A bare URL is not persistent: it is the single most common cause of a dead data link five years after publication. 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A dataset that needs a €2,000 licence to open is not reusable.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No file-format token (e.g., CSV, HDF5, FASTQ) is named for the released data.","gain":8.33,"priority":"important","scored":true},{"key":"x_code_availability","dimension":"R","label":"Analysis code available","action":"Publish the analysis code in a public forge, archive a tagged release with a DOI (Zenodo/Software Heritage), and cite that DOI in the paper. NIH DMS Element 2 asks for the tools and code, not only the data — and 'available on request' is not a locator. Archive the analysis code in a versioned repository (GitHub + a Zenodo release DOI).","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No code locator (repository URL, DOI, or package identifier) is provided; the only offer is not stated.","gain":8.33,"priority":"important","scored":true},{"key":"f_dataset_cited","dimension":"F","label":"Dataset formally cited","action":"Cite the dataset in the reference list like a publication — creator, year, title, repository, DOI/accession — and cite it in-text where it is used. Only a reference- list entry is machine-readable to Crossref/DataCite, and only a citation lets the data earn credit. Cite the clinical / human-subjects repository accession (e.g. from dbGaP or the European Genome-phenome Archive (EGA)) in the reference list.","anchors":["yes","partial","no"],"verdict":"partial","current":0.5,"evidence":"The 10× Cell Ranger filtered feature-barcode matrix data files and the scRNA-seq data are publicly available for download at https://zenodo.org/record/7942968 (accessed on 1 October 2025).","why":"The dataset identifier (Zenodo URL) appears only in the body text, not in the reference list.","gain":4.17,"priority":"important","scored":true},{"key":"r_versioning","dimension":"R","label":"Snapshot identified","action":"Version the deposit and cite the exact version analysed (a version-specific DOI, or an accession with its version suffix). 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A reporting checklist standardises your paper; it does nothing for your data. In clinical / human-subjects, describe the data with OMOP CDM, CDISC SDTM or HL7 FHIR.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No data or metadata community standard (e.g., MIAME, MINSEQE) is named; the paper uses only software tools and generic protocols.","gain":0.0,"priority":"important","scored":false},{"key":"r_documentation_codebook","dimension":"R","label":"Documentation / codebook","action":"Ship a README and a data dictionary IN the deposit — every file, every variable, its units, its allowed values, its missing-value codes. 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[majority verdict 'partial' (3/5 passes agreed)]","gain":0.0,"priority":"useful","scored":false}],"suggestions":["Attach a standard, machine-readable open licence to the deposit — CC0 or CC BY, which is what Horizon Europe and most funders expect — and print the licence identifier in the paper. 'Free to use' is not a licence: it grants nothing a reuser's institution can rely on.","Mint or cite a persistent identifier for the dataset — a repository DOI or an accession from a registered repository — and print it in the paper. A bare URL is not persistent: it is the single most common cause of a dead data link five years after publication. For clinical / human-subjects data, deposit in dbGaP or the European Genome-phenome Archive (EGA).","Release the data in an open, community-standard format (CSV/TSV, JSON, HDF5, NetCDF, FASTQ, VCF, NIfTI…) instead of — or alongside — any proprietary or instrument-native format, and name the format in the paper. A dataset that needs a €2,000 licence to open is not reusable.","Publish the analysis code in a public forge, archive a tagged release with a DOI (Zenodo/Software Heritage), and cite that DOI in the paper. NIH DMS Element 2 asks for the tools and code, not only the data — and 'available on request' is not a locator. Archive the analysis code in a versioned repository (GitHub + a Zenodo release DOI).","Cite the dataset in the reference list like a publication — creator, year, title, repository, DOI/accession — and cite it in-text where it is used. Only a reference- list entry is machine-readable to Crossref/DataCite, and only a citation lets the data earn credit. Cite the clinical / human-subjects repository accession (e.g. from dbGaP or the European Genome-phenome Archive (EGA)) in the reference list."],"model":"deepseek/deepseek-v4-flash","agent_version":"fair_agent_v8","fulltext_source":"epmc_xml"},"fair_model":"deepseek/deepseek-v4-flash","fair_agent_version":"fair_agent_v8","fair_fulltext_source":"epmc_xml","fair_has_llm":true,"fair_computed_at":"2026-07-20T13:51:38.114823Z","clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}