Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves’ disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ∼2.9 million genomes and identified 235 known and 501 novel independent variants significantly linked to thyroid diseases. We discovered genetic correlations between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases (r2=0.21-0.97). Telomere maintenance genes contribute to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair, and DNA damage response genes are predominantly associated with thyroid cancer. We proposed a paradigm explaining genetic predisposition to benign and malignant thyroid nodules. We evaluated thyroid cancer polygenic risk scores (PRS) for clinical applications in thyroid cancer diagnosis. We found PRS associations with thyroid cancer risk features: multifocality, lymph node metastases, and extranodal extension.

Nikita Pozdeyev and Bryan R. Haugen receive research support from Veracyte, Inc. unrelated to this study.

https://github.com/pozdeyevlab/gwas-analysis

This project was funded by the National Cancer Institute grant 1R21CA282380 to Nikita Pozdeyev, Bryan Haugen and Christopher Gignoux, and the Colorado Clinical and Translational Sciences Institute grant CO-J-24-170 to Nikita Pozdeyev. Lauren Fishbein is supported by the VA Merit Award I01BX006252. Tugce Karaderi is supported by the Novo Nordisk Foundation Data Science Emerging Investigator grant (NNF20OC0062294). Milton Pividori is supported by the National Human Genome Research Institute (R00HG011898). Genes & Health is/has recently been core-funded by Wellcome (WT102627, WT210561), the Medical Research Council (UK) (M009017, MR/X009777/1, MR/X009920/1), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). We acknowledge the support of the National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330); a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St George's University Hospitals NHS Foundation Trust and St George's University of London. Genes & Health is/has recently been funded by Alnylam Pharmaceuticals, Genomics PLC; and a Life Sciences Industry Consortium of AstraZeneca PLC, Bristol-Myers Squibb Company, GlaxoSmithKline Research and Development Limited, Maze Therapeutics Inc, Merck Sharp & Dohme LLC, Novo Nordisk A/S, Pfizer Inc, Takeda Development Centre Americas Inc.

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:

Colorado Multiple Institutional Review Board for the University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA, waived ethical approval for this work (COMIRB #20-2315).

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

The meta-analysis GWAS summary statistics will be deposited in the GWAS Catalog after the acceptance of this manuscript for peer-reviewed publication. The PRS weights will be deposited in the PGS Catalog (https://www.pgscatalog.org/). All original code is publicly available at GitHub at https://github.com/pozdeyevlab/gwas-analysis.

Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Nikita Pozdeyev, email: nikita.pozdeyevcuanschutz.edu.