Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases. ### Competing Interest Statement M.D.T. and L.V.W. have previously received funding from GSK for collaborative research projects outside of the submitted work. R.J.P., M.D.T., C.J. and L.V.W. have a funded research collaboration with Orion for collaborative research projects outside the submitted work. ### Funding Statement The research was partially supported by the NIHR Leicester Biomedical Research Centre and through an NIHR Senior Investigator Award to M.D. Tobin; views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the design of the study. This research was funded in whole, or in part, by the Wellcome Trust: Wellcome Trust Investigator Award (WT202849/Z/16/Z, MD Tobin) and Wellcome Trust Discovery Award (WT225221/Z/22/Z, MD Tobin and L.V.Wain). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. L. V. Wain was supported by GSK/British Lung Foundation Chair in Respiratory Research. C. Batini was supported by a UKRI Innovation Fellowship at Health Data Research UK (MR/S003762/1). C. John held a Medical Research Council Clinical Research Training Fellowship (MR/P00167X/1). EXCEED is supported by the University of Leicester, the NIHR Leicester Respiratory Biomedical Research Centre, by Wellcome [202849, https://doi.org/10.35802/202849] and by Cohort Access fees from studies funded by the Medical Research Council (MRC), BBRSC, NIHR, the UK Space Agency, and GSK. It was previously supported by MRC grant G0902313. This work is supported by BREATHE - The Health Data Research Hub for Respiratory Health [UKR\_PC\_19004] in partnership with SAIL Databank. We also thank all participants and staff who have contributed their time to the study. ### 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 UK Biobank genetic and phenotypic data were analysed under UK Biobank Application 43027. UK Biobank has ethical approval from the UK National Health Service (NHS) National Research Ethics Service (11/NW/0382). EXCEED received ethical approval from the Leicester Central Research Ethics Committee (13/EM/0226). The activities of the Estonian Biobank are regulated by the Human Genes Research Act, which was adopted in 2000 specifically for the operations of Estonian Biobank. Individual level data analysis in 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 6-7/GI/2013 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Genome-wide summary statistics will be deposited at GWAS Catalog (EMBL-EBI) upon acceptance of the manuscript.