GWAS meta-analysis and gene expression data link reproductive tract development, immune response and cellular proliferation/apoptosis with cervical cancer and clarify overlap with other cervical phenotypes

Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including up to 9,229 cases and 490,304 controls for cervical cancer from diverse ancestries. We prioritise PAX8/PAX8-AS1 , LINC00339 , CDC42 , CLPTM1L , HLA-DRB1 , and GSDMB as the most likely candidate genes for cervical cancer signals, providing insights into cervical cancer pathogenesis and supporting the involvement of reproductive tract development, immune response, and cellular proliferation/apoptosis. We construct a GRS that associates with cervical cancer (HR=3.7 for top 5% vs lowest 5%), and with other HPV- and immune-system related diagnoses in a PheWAS analysis. Our results propose valuable leads for further functional studies and the presented GRS offers an additional opportunity for risk stratification together with conventional screening strategies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by European Union through Horizon 2020 grant INTERVENE, the Estonian Research Council grants PRG687, PRG1291 and PSG776 and by MATER Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 813707. Computational analyses of Estonian Biobank data were performed in the High Performance Computing Center, University of Tartu. U.V was funded by the European Regional Development Fund and the programme Mobilitas Pluss (MOBTP108). The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, and Novartis AG. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank ([www.auria.fi/biopankki][1]), THL Biobank ([www.thl.fi/biobank][2]), Helsinki Biobank ([www.helsinginbiopankki.fi][3]), Biobank Borealis of Northern Finland (), Finnish Clinical Biobank Tampere ([www.tays.fi/en-US/Research\_and\_development/Finnish\_Clinical\_Biobank_Tampere][4]), Biobank of Eastern Finland ([www.ita-suomenbiopankki.fi/en][5]), Central Finland Biobank ([www.ksshp.fi/fi-FI/Potilaalle/Biopankki][6]), Finnish Red Cross Blood Service Biobank ([www.veripalvelu.fi/verenluovutus/biopankkitoiminta][7]) and Terveystalo Biobank ([www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/][8]). All Finnish Biobanks are members of BBMRI.fi infrastructure ([www.bbmri.fi][9]). Finnish Biobank Cooperative -FINBB () is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious® services () managed by FINBB. ### 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: All Estonian biobank participants have signed a broad informed consent form and the study was carried out under ethical approval 1.1-12/624 from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs). Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea, the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) approved the FinnGen study protocol Nr HUS/990/2017. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes FinnGen R5 data can be browsed and downloaded from . Biobank Japan data can be browsed and downloaded from . GWAS meta-analysis summary statistics will be made available upon publication of this manuscript. . [1]: http://www.auria.fi/biopankki [2]: http://www.thl.fi/biobank [3]: http://www.helsinginbiopankki.fi [4]: http://www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere [5]: http://www.ita-suomenbiopankki.fi/en [6]: http://www.ksshp.fi/fi-FI/Potilaalle/Biopankki [7]: http://www.veripalvelu.fi/verenluovutus/biopankkitoiminta [8]: http://www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/ [9]: http://www.bbmri.fi