Uncovering the Shared Genetic Components of Thyroid Disorders and Reproductive Health

Thyroid disorders are complex and polygenic, and thus result from the interaction of many genetic variants. Due to a central role of the thyroid hormones in the body, their dysfunction can have a significant impact on the reproductive health in men and women. Mapping the shared genetic component and relationships between thyroid and reproductive health traits will improve the understanding about the interplay between those domains. Here, a large-scale genetic analysis of thyroid traits (hyper- and hypothyroidism, and thyroid stimulating hormone levels) was conducted in up to 743,088 individuals of European ancestry from various cohorts. We evaluated genetic and phenotypic associations using genome-wide association study (GWAS) meta-analysis, gene prioritisation, genetic correlation analysis, and phenotype vs phenome-wide-association analysis. The results showed that 32% of thyroid-associated genes also had an impact on reproductive phenotypes, with the most affected functions being related to genitourinary tract issues. The study highlights the shared genetic determinants between thyroid function and reproductive health, providing evidence for the genetic pleiotropy between these traits in both men and women. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED, and by the Estonian Research Council grants 1911, PRG1844 and PRG1291. Natalia Pujol-Gualdo was supported by MATER Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 813707. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. ### 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: The activities of the Estonian Biobank are regulated by the Human Genes Research Act, which was adopted in 2000 specifically for the operations of the Estonian Biobank. Individual level data analysis in the Estonian Biobank was carried out under ethical approval 1.1-12/624 from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs), using data according to release application S53 from the Estonian Biobank. 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 All data produced in the present study are available upon reasonable request to the authors.