Genetic analysis of female genital tract polyps implicates genome stability, estrogen signalling and shared susceptibility with proliferative gynaecological disorders

Nathan Ingold, Ingold N, Frankcombe S, Stephanie Frankcombe, Bouttle K, Kelsie Bouttle, Moro E, Emily Moro, Daffodil M. Canson, Canson D, Zöllner S, Sebastian Zöllner, Patil S, Snehal Patil, Jelisaveta Džigurski, Džigurski J, Dylan M. Glubb, Glubb DM, Laisk T, Triin Laisk, Tracy A. O’Mara, O’Mara TA
In: medRxiv · 2026 · doi:10.64898/2026.04.13.26350740 · W7154588199
preprint OA: green CC0
🔓 Open OA copy Full text JSON View on OpenAlex View at publisher
⚙ AI-generated summary by claude@2026-07, 2026-07-09 ⓘ

This genome-wide association study identified 52 risk loci for female genital tract polyps, implicating impaired genome stability, estrogen signaling, and shared genetic susceptibility with other gynecological disorders.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by claude@2026-07, 2026-07-09 · read from full text ⓘ

This study investigated the genetic architecture of female genital tract (FGT) polyps using a genome-wide association study (GWAS) meta-analysis across four biobanks (48,400 cases and 477,134 controls), identifying 26 risk loci, including 12 novel signals, with 39 loci replicated in an independent cohort. Integrative gene prioritisation implicated convergent pathways linking germline variation in DNA replication/maintenance (e.g., PRIM1, TERT, HMGA1) to hormone-driven proliferation and estrogen signalling (e.g., ESR1, GREB1), with adiposity-related and estrogen-biosynthesis-related loci such as RSPO3, PLCE1, and CYP19A1. Mendelian randomisation supported bidirectional causal relationships between FGT polyp susceptibility and endometriosis, fibroids, and endometrial cancer, and multi-trait analysis added additional loci including sub-threshold regions around HMGA1 and GREB1, with the caveat that the work is based on genetic association and inference from summary statistics rather than direct mechanistic experiments in polyps. This paper is centrally about endometriosis and related gynaecological proliferative disorders through its Mendelian randomisation evidence for bidirectional endometriosis susceptibility and shared susceptibility loci, even though its primary phenotype focus is FGT polyps.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Abstract

Abstract Female genital tract (FGT) polyps are common benign growths affecting up to half of all women. However, they carry malignant potential, and their genetic architecture remains poorly defined. We conducted a genome-wide association study (GWAS) meta-analysis across four biobanks (48,400 cases, 477,134 controls), identifying 26 risk loci for FGT polyps, 12 of which were previously unreported. Integrative gene prioritisation highlighted 193 candidate genes, revealing a potential convergent biological mechanism: where germline variation in DNA replication and maintenance (e.g., PRIM1 , TERT and HMGA1 ) compromises genomic stability in the context of hormone-driven proliferation (e.g., ESR1 and GREB1 ). This susceptibility is further modulated by metabolic drivers of estrogen biosynthesis, underscored by specific adiposity-related loci (e.g. RSPO3 and PLCE1 ) and the aromatase gene CYP19A1 . Mendelian randomisation demonstrated bidirectional causal relationships with endometriosis and fibroids, and endometrial cancer. Leveraging the shared genetic architecture of FGT polyps and other gynaecological disorders via multi-trait analysis revealed an additional 26 loci, validating sub-threshold regions encompassing HMGA1 and GREB1. In total, 52 risk loci were identified (36 novel), 39 of which replicated in an independent cohort. These findings reframe polyps not merely as local gynaecological overgrowths but as manifestations of a systemic proliferative syndrome characterised by dysregulated genome stability and estrogen signalling, which may also impact malignant transformation.
Full text 5,053 characters · extracted from oa-html · click to expand
Abstract Female genital tract (FGT) polyps are common benign growths affecting up to half of all women. However, they carry malignant potential, and their genetic architecture remains poorly defined. We conducted a genome-wide association study (GWAS) meta-analysis across four biobanks (48,400 cases, 477,134 controls), identifying 26 risk loci for FGT polyps, 12 of which were previously unreported. Integrative gene prioritisation highlighted 193 candidate genes, revealing a potential convergent biological mechanism: where germline variation in DNA replication and maintenance (e.g., PRIM1, TERT and HMGA1) compromises genomic stability in the context of hormone-driven proliferation (e.g., ESR1 and GREB1). This susceptibility is further modulated by metabolic drivers of estrogen biosynthesis, underscored by specific adiposity-related loci (e.g. RSPO3 and PLCE1) and the aromatase gene CYP19A1. Mendelian randomisation demonstrated bidirectional causal relationships with endometriosis and fibroids, and endometrial cancer. Leveraging the shared genetic architecture of FGT polyps and other gynaecological disorders via multi-trait analysis revealed an additional 26 loci, validating sub-threshold regions encompassing HMGA1 and GREB1. In total, 52 risk loci were identified (36 novel), 39 of which replicated in an independent cohort. These findings reframe polyps not merely as local gynaecological overgrowths but as manifestations of a systemic proliferative syndrome characterised by dysregulated genome stability and estrogen signalling, which may also impact malignant transformation. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Investigator Grants (APP1173170 and #ID 2041819) awarded to T.A.OM, and an NHMRC Project Grant (APP1158083) awarded to T.A.OM and D.M.G. K.B. is supported by a QIMR Berghofer Cancer Genetic Susceptibility PhD Scholarship and a University of Queensland Research Training Scholarship. T.L and J.D was supported by the Estonian Research Council grant PSG776. S.F was supported by the QIMR Berghofer Vocational Research Scholarship. The funders had no role in study design, data collection and analysis, interpretation of results, or manuscript preparation. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UKBB participants gave informed consent provided under the ethical approval of the Northwest Multi-centre Research Ethics Committee. This project used data from the UKBB under application number 25331. All Estonian Biobank participants have signed a broad informed consent for using their data in research, and the study was carried out under ethical approval from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs). FinnGen Participants gave informed consent under the ethical approval of the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa. For this study, we downloaded the publicly available summary statistics from the FinnGen data portal Release 11. Participants provided informed consent under ethical approval from The University of Michigan Medical School Institutional Review Board. We accessed GWAS summary statistics of the MGI data for freeze 3. All of Us participant data was collected with informed consent under the ethical approval and ongoing oversight of the All of Us Institutional Review Board. We accessed and analysed controlled tier short read whole genome sequencing data through the online All of Us researcher workbench. This study was conducted under the ethical approval of the QIMR Berghofer ethics committee (P1051). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability GWAS summary statistics will be made publically available on Zenodo at time of publication.

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: oa-html ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

endometriosis

Citation neighborhood (sparse)

Too few in-corpus citations on either side for a chart; here are the lists.

Cites (3)

References (60)

Source provenance

europepmc
last seen: 2026-07-27T06:53:59.744402+00:00
openalex
last seen: 2026-07-16T06:07:44.659526+00:00
License: CC0 · commercial use OK