Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Rosalie B. T. M. Sterenborg, Inga Steinbrenner, Yong Li, Melissa N. Bujnis, Tatsuhiko Naito, Eirini Marouli, Tessel E. Galesloot, Oladapo Babajide, Laura Andreasen, Arne Astrup, Bjørn Olav Åsvold, Stefania Bandinelli, Marian Beekman, John P. Beilby, Jette Bork-Jensen, Thibaud Boutin, Jennifer A. Brody, Suzanne J. Brown, Ben Brumpton, Purdey J. Campbell, Anne R. Cappola, Graziano Ceresini, Layal Chaker, Daniel I. Chasman, Maria Pina Concas, Rodrigo Coutinho de Almeida, Simone M. Cross, Francesco Cucca, Ian J. Deary, Alisa Devedzic Kjaergaard, Justin B. Echouffo Tcheugui, Christina Ellervik, Johan G. Eriksson, Luigi Ferrucci, Jan Freudenberg, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E. Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N. Harding, Sarah E. Harris, Stig Haunsø, Caroline Hayward, Jennie Hui, Till Ittermann, J. Wouter Jukema, Eero Kajantie, Jørgen K. Kanters, Line L. Kårhus, Lambertus A. L. M. Kiemeney, Margreet Kloppenburg, Brigitte Kühnel, Jari Lahti, Claudia Langenberg, Bruno Lapauw, Graham Leese, Shuo Li, David C. M. Liewald, Allan Linneberg, Jesus V. T. Lominchar, Jian’an Luan, Nicholas G. Martin, Antonela Matana, Marcel E. Meima, Thomas Meitinger, Ingrid Meulenbelt, Braxton D. Mitchell, Line T. Møllehave, Samia Mora, Silvia Naitza, Matthias Nauck, Romana T. Netea-Maier, Raymond Noordam, Casia Nursyifa, Yukinori Okada, Stefano Onano, Areti Papadopoulou, Colin N. A. Palmer, Cristian Pattaro, Oluf Pedersen, Annette Peters, Maik Pietzner, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Ante Punda, Debashree Ray, Paul Redmond, J. Brent Richards, Paul M. Ridker, Tom C. Russ, Kathleen A. Ryan, Morten Salling Olesen, Ulla T. Schultheiss, Elizabeth Selvin, Moneeza K. Siddiqui, Carlo Sidore, P. Eline Slagboom, Thorkild I. A. Sørensen, Enrique Soto-Pedre, Tim D. Spector, Beatrice Spedicati, Sundararajan Srinivasan, John M. Starr, David J. Stott, Toshiko Tanaka, Vesela Torlak, Stella Trompet, Johanna Tuhkanen, André G. Uitterlinden, Erik B. Akker, Tibbert Eynde, Melanie M. Klauw, Diana Heemst, Charlotte Verroken, W. Edward Visser, Dina Vojinovic, Henry Völzke, Melanie Waldenberger, John P. Walsh, Nicholas J. Wareham, Stefan Weiss, Cristen J. Willer, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Hanneke J. C. M. Wouters, Margaret J. Wright, Qiong Yang, Tatijana Zemunik, Wei Zhou, Gu Zhu, Sebastian Zöllner, Johannes W. A. Smit, Robin P. Peeters, Anna Köttgen, Alexander Teumer () and Marco Medici ()
Additional contact information
Rosalie B. T. M. Sterenborg: Radboud University Medical Center
Inga Steinbrenner: Faculty of Medicine and Medical Center - University of Freiburg
Yong Li: Faculty of Medicine and Medical Center - University of Freiburg
Melissa N. Bujnis: The University of Utah
Tatsuhiko Naito: Osaka University Graduate School of Medicine
Eirini Marouli: Queen Mary University of London
Tessel E. Galesloot: Radboud University Medical Center
Oladapo Babajide: Queen Mary University of London
Laura Andreasen: Copenhagen University Hospital - Rigshospitalet
Arne Astrup: The Novo Nordisk Foundation
Bjørn Olav Åsvold: NTNU, Norwegian University of Science and Technology
Stefania Bandinelli: Geriatric Unit, Azienda Sanitaria Toscana Centro
Marian Beekman: Leiden University Medical Center
John P. Beilby: The University of Western Australia
Jette Bork-Jensen: University of Copenhagen
Thibaud Boutin: University of Edinburgh, Western General Hospital
Jennifer A. Brody: University of Washington
Suzanne J. Brown: Sir Charles Gairdner Hospital
Ben Brumpton: NTNU, Norwegian University of Science and Technology
Purdey J. Campbell: Sir Charles Gairdner Hospital
Anne R. Cappola: University of Pennsylvania
Graziano Ceresini: University of Parma
Layal Chaker: Erasmus Medical Center
Daniel I. Chasman: Brigham and Women’s Hospital
Maria Pina Concas: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Rodrigo Coutinho de Almeida: Leiden University Medical Center
Simone M. Cross: QIMR Berghofer Medical Research Institute
Francesco Cucca: Consiglio Nazionale delle Ricerche
Ian J. Deary: University of Edinburgh
Alisa Devedzic Kjaergaard: Aarhus University Hospital
Justin B. Echouffo Tcheugui: Johns Hopkins School of Medicine
Christina Ellervik: Harvard Medical School
Johan G. Eriksson: University of Helsinki
Luigi Ferrucci: Longitudinal Study Section, National Institute on Aging
Jan Freudenberg: Regeneron Pharmaceuticals, Inc., Tarrytown
Christian Fuchsberger: Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
Christian Gieger: Institute of Epidemiology, Helmholtz Zentrum München
Franco Giulianini: Brigham and Women’s Hospital
Martin Gögele: Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
Sarah E. Graham: Cardiology, University of Michigan
Niels Grarup: University of Copenhagen
Ivana Gunjača: University of Split, School of Medicine
Torben Hansen: University of Copenhagen
Barbara N. Harding: University of Washington
Sarah E. Harris: University of Edinburgh
Stig Haunsø: Copenhagen University Hospital - Rigshospitalet
Caroline Hayward: University of Edinburgh, Western General Hospital
Jennie Hui: Pathwest Laboratory Medicine WA
Till Ittermann: University Medicine Greifswald
J. Wouter Jukema: Leiden University Medical Center
Eero Kajantie: Population Health Unit, Helsinki and Oulu
Jørgen K. Kanters: University of Copenhagen
Line L. Kårhus: Bispebjerg and Frederiksberg Hospital
Lambertus A. L. M. Kiemeney: Radboud University Medical Center
Margreet Kloppenburg: Leiden University Medical Center
Brigitte Kühnel: Institute of Epidemiology, Helmholtz Zentrum München
Jari Lahti: University of Helsinki
Claudia Langenberg: University of Cambridge School of Clinical Medicine
Bruno Lapauw: Ghent University Hospital, C. Heymanslaan 10
Graham Leese: NHS Tayside
Shuo Li: Boston University
David C. M. Liewald: University of Edinburgh
Allan Linneberg: University of California San Francisco
Jesus V. T. Lominchar: University of Copenhagen
Jian’an Luan: University of Cambridge School of Clinical Medicine
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Antonela Matana: University of Split, School of Medicine
Marcel E. Meima: Erasmus Medical Center
Thomas Meitinger: Technical University of Munich
Ingrid Meulenbelt: Leiden University Medical Center
Braxton D. Mitchell: University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition
Line T. Møllehave: Bispebjerg and Frederiksberg Hospital
Samia Mora: Brigham and Women’s Hospital
Silvia Naitza: Consiglio Nazionale delle Ricerche
Matthias Nauck: DZHK (German Center for Cardiovascular Research), partner site Greifswald
Romana T. Netea-Maier: Radboud University Medical Center
Raymond Noordam: Leiden University Medical Center
Casia Nursyifa: University of Copenhagen
Yukinori Okada: Osaka University Graduate School of Medicine
Stefano Onano: Consiglio Nazionale delle Ricerche
Areti Papadopoulou: Queen Mary University of London
Colin N. A. Palmer: School of Medicine, University of Dundee
Cristian Pattaro: Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
Oluf Pedersen: University of Copenhagen
Annette Peters: German Research Center for Environmental Health
Maik Pietzner: University of Cambridge School of Clinical Medicine
Ozren Polašek: University of Split, School of Medicine
Peter P. Pramstaller: Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
Bruce M. Psaty: University of Washington
Ante Punda: University Hospital Split
Debashree Ray: Johns Hopkins Bloomberg School of Public Health
Paul Redmond: University of Edinburgh
J. Brent Richards: Jewish General Hospital, Montreal
Paul M. Ridker: Brigham and Women’s Hospital
Tom C. Russ: University of Edinburgh
Kathleen A. Ryan: University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition
Morten Salling Olesen: Copenhagen University Hospital - Rigshospitalet
Ulla T. Schultheiss: Faculty of Medicine and Medical Center - University of Freiburg
Elizabeth Selvin: Johns Hopkins Bloomberg School of Public Health
Moneeza K. Siddiqui: Queen Mary University of London
Carlo Sidore: Consiglio Nazionale delle Ricerche
P. Eline Slagboom: Leiden University Medical Center
Thorkild I. A. Sørensen: University of Copenhagen
Enrique Soto-Pedre: School of Medicine, University of Dundee
Tim D. Spector: King’s College London, St Thomas’ Campus
Beatrice Spedicati: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Sundararajan Srinivasan: School of Medicine, University of Dundee
John M. Starr: University of Edinburgh
David J. Stott: University of Glasgow
Toshiko Tanaka: Longitudinal Study Section, National Institute on Aging
Vesela Torlak: University Hospital Split
Stella Trompet: Leiden University Medical Center
Johanna Tuhkanen: University of Helsinki
André G. Uitterlinden: Erasmus Medical Center
Erik B. Akker: Leiden University Medical Center
Tibbert Eynde: Precision Healthcare University Research Institute, Queen Mary University of London
Melanie M. Klauw: University of Groningen, University Medical Center Groningen
Diana Heemst: Leiden University Medical Center
Charlotte Verroken: Ghent University Hospital, C. Heymanslaan 10
W. Edward Visser: Erasmus Medical Center
Dina Vojinovic: Leiden University Medical Center
Henry Völzke: University Medicine Greifswald
Melanie Waldenberger: Institute of Epidemiology, Helmholtz Zentrum München
John P. Walsh: Sir Charles Gairdner Hospital
Nicholas J. Wareham: University of Cambridge School of Clinical Medicine
Stefan Weiss: DZHK (German Center for Cardiovascular Research), partner site Greifswald
Cristen J. Willer: Cardiology, University of Michigan
Scott G. Wilson: The University of Western Australia
Bruce H. R. Wolffenbuttel: University of Groningen, University Medical Center Groningen
Hanneke J. C. M. Wouters: University of Groningen, University Medical Center Groningen
Margaret J. Wright: University of Queensland
Qiong Yang: Boston University
Tatijana Zemunik: University of Split, School of Medicine
Wei Zhou: Massachusetts General Hospital
Gu Zhu: QIMR Berghofer Medical Research Institute
Sebastian Zöllner: University of Michigan
Johannes W. A. Smit: Radboud University Medical Center
Robin P. Peeters: Erasmus Medical Center
Anna Köttgen: Faculty of Medicine and Medical Center - University of Freiburg
Alexander Teumer: University Medicine Greifswald
Marco Medici: Radboud University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Date: 2024
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DOI: 10.1038/s41467-024-44701-9

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