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

Author

Listed:
  • Rosalie B. T. M. Sterenborg

    (Radboud University Medical Center
    Erasmus 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
    RIKEN Center for Integrative Medical Sciences)

  • Eirini Marouli

    (Queen Mary University of London
    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
    University of Copenhagen)

  • Arne Astrup

    (The Novo Nordisk Foundation)

  • Bjørn Olav Åsvold

    (NTNU, Norwegian University of Science and Technology
    Trondheim University Hospital)

  • 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
    Norwegian University of Science and Technology)

  • Purdey J. Campbell

    (Sir Charles Gairdner Hospital)

  • Anne R. Cappola

    (University of Pennsylvania)

  • Graziano Ceresini

    (University of Parma
    Azienda Ospedaliero-Universitaria di Parma)

  • Layal Chaker

    (Erasmus Medical Center
    University Medical Centre
    Harvard T.H. Chan School of Public Health)

  • Daniel I. Chasman

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • 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
    Università di Sassari, Dipartimento di Scienze Biomediche, V.le San Pietro)

  • 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
    University of Copenhagen
    Boston Children’s Hospital
    Zealand University Hospital)

  • Johan G. Eriksson

    (University of Helsinki
    National University Singapore, Yong Loo Lin School of Medicine, Department of Obstetrics and Gynecology)

  • 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
    Barcelona Institute for Global Health)

  • Sarah E. Harris

    (University of Edinburgh)

  • Stig Haunsø

    (Copenhagen University Hospital - Rigshospitalet
    University of Copenhagen)

  • Caroline Hayward

    (University of Edinburgh, Western General Hospital)

  • Jennie Hui

    (Pathwest Laboratory Medicine WA
    The University of Western Australia)

  • Till Ittermann

    (University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), partner site Greifswald)

  • J. Wouter Jukema

    (Leiden University Medical Center
    Netherlands Heart Institute)

  • Eero Kajantie

    (Population Health Unit, Helsinki and Oulu
    Oulu University Hospital and University of Oulu
    Norwegian University of Science and Technology)

  • Jørgen K. Kanters

    (University of Copenhagen
    University of California San Francisco)

  • Line L. Kårhus

    (Bispebjerg and Frederiksberg Hospital)

  • Lambertus A. L. M. Kiemeney

    (Radboud University Medical Center
    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
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin
    Precision Healthcare University Research Institute, Queen Mary University of London)

  • 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
    University of Copenhagen)

  • 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
    Baltimore Veterans Administration Medical Center)

  • Line T. Møllehave

    (Bispebjerg and Frederiksberg Hospital)

  • Samia Mora

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • Silvia Naitza

    (Consiglio Nazionale delle Ricerche)

  • Matthias Nauck

    (DZHK (German Center for Cardiovascular Research), partner site Greifswald
    University Medicine 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
    RIKEN Center for Integrative Medical Sciences
    Graduate School of Medicine, the University of Tokyo
    Immunology Frontier Research Center (WPI-IFReC), Osaka University)

  • 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
    Herlev-Gentofte University Hospital)

  • Annette Peters

    (German Research Center for Environmental Health
    Ludwig-Maximilians-Universität München)

  • Maik Pietzner

    (University of Cambridge School of Clinical Medicine
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin
    Precision Healthcare University Research Institute, Queen Mary University of London)

  • Ozren Polašek

    (University of Split, School of Medicine
    Algebra University College)

  • Peter P. Pramstaller

    (Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research)

  • Bruce M. Psaty

    (University of Washington
    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
    Harvard Medical School)

  • Tom C. Russ

    (University of Edinburgh
    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
    University of Copenhagen)

  • Ulla T. Schultheiss

    (Faculty of Medicine and Medical Center - University of Freiburg
    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
    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”
    University of Trieste)

  • 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
    Leiden University Medical Center)

  • Johanna Tuhkanen

    (University of Helsinki)

  • André G. Uitterlinden

    (Erasmus Medical Center)

  • Erik B. Akker

    (Leiden University Medical Center
    Leiden University Medical Center
    Delft University of Technology)

  • 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
    University Medical Centre)

  • Henry Völzke

    (University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), partner site Greifswald)

  • Melanie Waldenberger

    (Institute of Epidemiology, Helmholtz Zentrum München)

  • John P. Walsh

    (Sir Charles Gairdner Hospital
    The University of Western Australia)

  • Nicholas J. Wareham

    (University of Cambridge School of Clinical Medicine)

  • Stefan Weiss

    (DZHK (German Center for Cardiovascular Research), partner site Greifswald
    University Medicine Greifswald)

  • Cristen J. Willer

    (Cardiology, University of Michigan)

  • Scott G. Wilson

    (The University of Western Australia
    Sir Charles Gairdner Hospital
    King’s College London, St Thomas’ Campus)

  • 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
    University Hospital Split)

  • Wei Zhou

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • Gu Zhu

    (QIMR Berghofer Medical Research Institute)

  • Sebastian Zöllner

    (University of Michigan
    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
    Johns Hopkins Bloomberg School of Public Health
    Albert-Ludwigs-Universität Freiburg)

  • Alexander Teumer

    (University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), partner site Greifswald
    University Medicine Greifswald
    Medical University of Bialystok)

  • Marco Medici

    (Radboud University Medical Center
    Erasmus Medical Center)

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.

Suggested Citation

  • 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 Å, 2024. "Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44701-9
    DOI: 10.1038/s41467-024-44701-9
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