Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
| Title: | Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases. |
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| Authors: | White SL; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Brasher MS; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Pattee J; Center for Innovative Design & Analysis, Colorado School of Public Health, University of Colorado Anschutz, Aurora, CO, USA.; Zhou W; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Chapman S; The Broad Institute, Cambridge, MA, USA.; Jee YH; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Bell CC; Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz, Aurora, CO, USA.; Jamil TL; Department of Otolaryngology, Head and Neck Surgery, University of Colorado Anschutz, Aurora, CO, USA.; Barrio M; Division of GI, Trauma, and Endocrine Surgery, Department of Surgery, University of Colorado Anschutz, Aurora, CO, USA.; Arehart CH; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.; Department of Ecology & Evolutionary Biology, University of Colorado Boulder, Boulder, CO, USA.; Evans LM; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.; Department of Ecology & Evolutionary Biology, University of Colorado Boulder, Boulder, CO, USA.; Hirbo J; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.; Cox NJ; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.; Straub P; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.; Namba S; Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Bertucci-Richter E; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.; Guare L; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Edris A; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Morris S; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Mulford AJ; Genomic Health Initiative, Endeavor Health Research Institute, Evanston, IL, USA.; Zhang H; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Fennessy B; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Tobin MD; Division of Public Health and Epidemiology, University of Leicester, Leicester, UK.; University Hospitals of Leicester NHS Trust, Leicester, UK.; Chen J; Division of Public Health and Epidemiology, University of Leicester, Leicester, UK.; Williams AT; Division of Public Health and Epidemiology, University of Leicester, Leicester, UK.; John C; Division of Public Health and Epidemiology, University of Leicester, Leicester, UK.; University Hospitals of Leicester NHS Trust, Leicester, UK.; van Heel DA; Blizard Institute, Queen Mary University of London, London, UK.; Mathur R; Wolfson Institute of Population Health, Queen Mary University of London, London, UK.; Finer S; Wolfson Institute of Population Health, Queen Mary University of London, London, UK.; Moksnes MR; HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.; Brumpton BM; HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.; Åsvold BO; HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.; Peculis R; Latvian Biomedical Research and Study Centre, Riga, Latvia.; Rovite V; Latvian Biomedical Research and Study Centre, Riga, Latvia.; Konrade I; Department of Internal Medicine, Riga Stradins University, Riga, Latvia.; Wang Y; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Crooks K; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Chavan S; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Fisher MJ; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Rafaels N; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Lin M; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Shortt JA; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Sanders AR; Genomic Health Initiative, Endeavor Health Research Institute, Evanston, IL, USA.; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.; Whiteman DC; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; MacGregor S; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; Medland SE; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; Thorsteinsdóttir U; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Stefánsson K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Karaderi T; Department of Public Health, Faculty of Health and Medical Sciences, Center for Health Data Science, Section for Health Data Science and Artificial Intelligence, University of Copenhagen, Copenhagen, Denmark.; Egan KM; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.; Bocklage T; University of Kentucky Markey Cancer Center, Lexington, KY, USA.; University of Kentucky-Department of Pathology and Laboratory Medicine, University of Kentucky-Chandler Medical Center, Lexington, KY, USA.; McCrary HC; University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA.; Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Riedlinger G; Rutgers Cancer Institute, New Brunswick, NJ, USA.; Salhia B; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Shriver C; Murtha Cancer Center, Uniformed Services University/Walter Reed National Military Medical Center, Bethesda, MD, USA.; Phan MD; University of Oklahoma Stephenson Cancer Center, Oklahoma City, OK, USA.; Medical Oncology/Head and Neck Oncology, Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.; Farlow JL; Indiana University School of Medicine, Indianapolis, IN, USA.; Edge S; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.; Departments of Surgical Oncology and Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.; Kaur V; University of Virginia Cancer Center, Charlottesville, VA, USA.; Department of Internal Medicine, Division of Hematology & Oncology, University of Virginia Health, Charlottesville, VA, USA.; Churchman ML; Aster Insights, Hudson, FL, USA.; Rounbehler RJ; Aster Insights, Hudson, FL, USA.; Brock PL; The Ohio State University Comprehensive Cancer Center and the Ohio State University College of Medicine, Columbus, OH, USA.; Ringel MD; The Ohio State University Comprehensive Cancer Center and the Ohio State University College of Medicine, Columbus, OH, USA.; Department of Molecular Medicine and Therapeutics, The Ohio State University Comprehensive Cancer Center and the Ohio State University College of Medicine, Columbus, OH, USA.; Pividori M; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.; Human Medical Genetics and Genomics Program, University of Colorado Anschutz, Aurora, CO, USA.; Schweppe R; Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz, Aurora, CO, USA.; University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, CO, USA.; Raeburn CD; Division of GI, Trauma, and Endocrine Surgery, Department of Surgery, University of Colorado Anschutz, Aurora, CO, USA.; Walters RG; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Chen Z; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Li L; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China.; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.; Matsuda K; Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.; Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.; Okada Y; Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Zöllner S; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.; Verma A; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Preuss MH; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Kenny E; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Hendricks AE; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Fishbein L; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz, Aurora, CO, USA.; University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, CO, USA.; Research Service, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.; Kraft P; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.; Daly MJ; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Neale BM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Martin AR; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Cole JB; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.; Human Medical Genetics and Genomics Program, University of Colorado Anschutz, Aurora, CO, USA.; Haugen BR; Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz, Aurora, CO, USA.; University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, CO, USA.; Gignoux CR; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA. chris.gignoux@cuanschutz.edu.; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA. chris.gignoux@cuanschutz.edu.; Human Medical Genetics and Genomics Program, University of Colorado Anschutz, Aurora, CO, USA. chris.gignoux@cuanschutz.edu.; University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, CO, USA. chris.gignoux@cuanschutz.edu.; Pozdeyev N; Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA. nikita.pozdeyev@cuanschutz.edu.; Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz, Aurora, CO, USA. nikita.pozdeyev@cuanschutz.edu.; Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA. nikita.pozdeyev@cuanschutz.edu.; University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, CO, USA. nikita.pozdeyev@cuanschutz.edu. |
| Corporate Authors: | Penn Medicine BioBank; Virtual Thyroid Biopsy Consortium; Colorado Center for Personalized Medicine; Genes & Health Research Team; BioBank Japan Project; Global Biobank Meta-analysis Initiative |
| Source: | Nature genetics [Nat Genet] 2026 Feb; Vol. 58 (2), pp. 307-316. Date of Electronic Publication: 2026 Feb 05. |
| Publication Type: | Journal Article; Meta-Analysis |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York, NY : Nature Pub. Co., c1992- |
| MeSH Terms: | Thyroid Neoplasms*/genetics ; Thyroid Neoplasms*/pathology ; Thyroid Diseases*/genetics ; Genome-Wide Association Study* ; Genetic Predisposition to Disease*; Multifactorial Inheritance/genetics ; Graves Disease/genetics ; Humans ; Polymorphism, Single Nucleotide |
| 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.; (© 2026. The Author(s).) |
| Competing Interests: | Competing interests: N.P. and B.R.H. received research support from Veracyte, unrelated to this study. B.R.H. is the Clinical Liaison for ThyroSeq at Sonic Healthcare USA. N.P., S.L.W., B.R.H. and C.R.G. filed a provisional patent application 151077-00053PR2 with the United States Patent and Trademark Office dedicated to the use of a PRS for ThC diagnosis. The other authors declare no competing interests. |
| Comments: | Update of: medRxiv. 2025 May 16:2025.05.15.25327513. doi: 10.1101/2025.05.15.25327513.. (PMID: 40463558) |
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| Grant Information: | R00HG011898 U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI); R00 HG011898 United States HG NHGRI NIH HHS; I01 BX006252 United States BX BLRD VA; CO-J-24-170 Colorado University | UC Denver | Colorado Clinical and Translational Sciences Institute (CCTSI); R21 CA282380 United States CA NCI NIH HHS; United Kingdom WT_ Wellcome Trust; UL1 TR002535 United States TR NCATS NIH HHS; R00 HG012222 United States HG NHGRI NIH HHS; 1R21CA282380 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); R01 AG046938 United States AG NIA NIH HHS; R25 DC021948 United States DC NIDCD NIH HHS; P30 CA177558 United States CA NCI NIH HHS; NNF20OC0062294 Novo Nordisk Fonden (Novo Nordisk Foundation) |
| Contributed Indexing: | Investigator: DA van Heel |
| Entry Date(s): | Date Created: 20260205 Date Completed: 20260212 Latest Revision: 20260402 |
| Update Code: | 20260402 |
| PubMed Central ID: | PMC12900643 |
| DOI: | 10.1038/s41588-025-02483-w |
| PMID: | 41644669 |
| Database: | MEDLINE |
Journal Article; Meta-Analysis