{"paper_id":"df5366a7-d80a-419c-9934-2e5bd647ed04","body_text":"Abstract\nFemale 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.\nCompeting Interest Statement\nThe authors have declared no competing interest.\nFunding Statement\nThis 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.\nAuthor Declarations\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\nYes\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\nUKBB 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).\nI 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.\nYes\nI 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).\nYes\nI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.\nYes\nData Availability\nGWAS summary statistics will be made publically available on Zenodo at time of publication.","source_license":"CC0","license_restricted":false}