Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Thyroid diseases are common and highly heritable. We performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer (ThC), benign nodular goiter, Graves' disease, lymphocytic thyroiditis and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 313 known and 570 new independent loci linked to thyroid diseases. We discovered genetic correlations between ThC, benign nodular goiter and autoimmune thyroid diseases (rg = 0.16-0.97). Telomere maintenance genes contributed to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair and damage response genes were associated with ThC. We propose a paradigm that explains genetic predisposition to benign and malignant thyroid nodules. We found polygenic risk score associations with ThC risk of structural disease recurrence, tumor size, multifocality, lymph node metastases and extranodal extension. Polygenic risk scores identified individuals with aggressive ThC in a biobank, creating an opportunity for genetically informed population screening.

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Publication Details

Journal
Nature Genetics
Published
2026-02-01
DOI
https://doi.org/10.1038/s41588-025-02483-w
Citations
2
Primary Topic
Thyroid Cancer Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
61.46

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article

Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Christopher H. Arehart, Meng Lin, Gregory Riedlinger, Ilze Konrāde et al.
2 citations
Nature Genetics
Thyroid Cancer Diagnosis and Treatment
61.46
article

Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Christopher H. Arehart, Meng Lin, Gregory Riedlinger, Ilze Konrāde, Nikita Pozdeyev Pozdeyev, Ahmed Edris, Milton Pividori, Emily M. Bertucci, Robert J. Rounbehler, Maizy S. Brasher, Samantha White, Bodour Salhia, Audrey E. Hendricks, C. Bridges John, Hilary C. McCrary, Lauren Fishbein, J Chen, Z Chen, Michelle L. Churchman, Rebecca E. Schweppe, Pamela Brock, C. R. Gignoux, CD Shriver, P. Straub, W Zhou, Kristy Crooks, Taylor L. Jamil, Lindsay Guare, Brian Fennessy, Luke M. Evans, Tugce Karaderi, Varinder Kaur, B. Haugen, Marta R. Moksnes, Jack Pattee, Lei Li, Martin Barrio, Matthew J. Fisher, A R Sanders, Yon Ho Jee, Christopher D. Raeburn, Karen A. Hunt, Sameer Chavan, Stephen B. Edge, Joanne B. Cole, Martin D. Tobin, Sam Morris, Rohini Mathur, Ying Wang, Matthew D. Ringel, Sarah Finer, Sebastian Zöllner, Koichi Matsuda, Peter Kraft, Kathleen M. Egan, Therese Bocklage, Caitlin C. Bell, Alicia R. Martin, Sarah E. Medland, Janice L. Farlow, Global Biobank Meta-analysis Initiative, Vita Rovite, Robin G. Walters, Ben M. Brumpton, Haoyu Zhang, Unnur Thorsteinsdóttir, Benjamin M. Neale, Sinéad Chapman, Eimear Kenny, The BioBank Japan Project, Yukinori Okada, Penn Medicine BioBank, Kári Stefánsson, David C. Whiteman, Anurag Verma, Raitis Peculis, Ashley J. Mulford, Mark J. Daly, David A. van Heel, Nicholas Rafaels, Minh D. Phan, Michael H. Preuss, Bjørn Olav Åsvold, Jibril Hirbo
article en
2 citations

Abstract

Thyroid diseases are common and highly heritable. We performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer (ThC), benign nodular goiter, Graves' disease, lymphocytic thyroiditis and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 313 known and 570 new independent loci linked to thyroid diseases. We discovered genetic correlations between ThC, benign nodular goiter and autoimmune thyroid diseases (rg = 0.16-0.97). Telomere maintenance genes contributed to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair and damage response genes were associated with ThC. We propose a paradigm that explains genetic predisposition to benign and malignant thyroid nodules. We found polygenic risk score associations with ThC risk of structural disease recurrence, tumor size, multifocality, lymph node metastases and extranodal extension. Polygenic risk scores identified individuals with aggressive ThC in a biobank, creating an opportunity for genetically informed population screening.

Nature GeneticsVol. 58(2)
Rutgers, The State University of New Jersey (US), Broad Institute (US), University of Southern California (US), University of Copenhagen (DK), Roswell Park Comprehensive Cancer Center (US), deCODE Genetics (Iceland) (IS), Harvard University (US), Latvian Biomedical Research and Study Centre (LV), University of Kentucky (US), Colorado School of Public Health (US), University of Leicester (GB), University of Iceland (IS), Queen Mary University of London (GB), University of Colorado Boulder (US), Peking University (CN), Norwegian University of Science and Technology (NO), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), University of Michigan (US), University of Virginia Health System (US), Walter Reed National Military Medical Center (US), Levanger Hospital (NO), Albert B. Chandler Hospital (US), Huntsman Cancer Institute (US), Markey Cancer Center (US), University Hospitals of Leicester NHS Trust (GB), University of Oklahoma Medical Center (US), Moffitt Cancer Center (US), University of Oxford (GB), University of Chicago (US), Massachusetts General Hospital (US), St Olav's University Hospital (NO), Riga Stradiņš University (LV), Oklahoma State University Oklahoma City (US), University of Colorado Cancer Center (US), National Cancer Institute (US), RIKEN Center for Integrative Medical Sciences (JP), Genomic Health (United States) (US), Department of Health and Human Services (US), University of Virginia Cancer Center, Indiana University School of Medicine, University of Virginia (US), University of Colorado Anschutz Medical Campus (US), The Ohio State University (US), Indiana University – Purdue University Indianapolis (US), The University of Tokyo (JP), University of Pennsylvania (US), University of Oklahoma (US), Vanderbilt University Medical Center (US), University of Colorado Denver (US), The University of Osaka (JP), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Health and Human Services, Roswell Park Cancer Institute, Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Massachusetts General Hospital, University of Southern California, Alnylam Pharmaceuticals, Ohio State University, Stiftelsen Kristian Gerhard Jebsen, University of Oklahoma, Norges Teknisk-Naturvitenskapelige Universitet, Queen Mary University of London, Regeneron Pharmaceuticals, Huntsman Cancer Institute, School of Public Health, University of Michigan, QIMR Berghofer Medical Research Institute, Broad Institute, Barts Charity, Georgia Clinical and Translational Science Alliance, UVA Cancer Center, Maze Therapeutics, National Institute for Health and Care Research, Department of Health and Social Care, King's College London, Public Health England, Novo Nordisk, Helse Midt-Norge, University of Tokyo, Háskóli Íslands, Norges Forskningsråd, Peking University, Faculty of Health and Medical Sciences, University of Western Australia, Novo Nordisk Fonden, St. Olavs Hospital Universitetssykehuset i Trondheim, St George's University Hospitals NHS Foundation Trust, Barts Health NHS Trust, National Institutes of Health, Uniformed Services University of the Health Sciences, Medical School, University of Michigan, School of Medicine, Indiana University, Walter Reed National Military Medical Center, Cancer Center, University of Colorado, Stephenson Cancer Center, Fakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige Universitet, Medical Research Council, National Health and Medical Research Council, Institute of Medical Science, University of Tokyo, NIHR Leicester Biomedical Research Centre, Graduate School of Frontier Sciences, University of Tokyo, Faculty of Medicine and Health, University of Sydney, Norwegian Institute of Public Health, National Human Genome Research Institute, National Cancer Institute, National Center for Advancing Translational Sciences, Colorado Clinical and Translational Sciences Institute, Division of Cancer Epidemiology and Genetics, National Cancer Institute
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Thyroid Cancer Diagnosis and Treatment
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