Nature Communications (Jan 2024)
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,
- GHS DiscovEHR,
- Regeneron Genetics Center,
- 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. van den Akker,
- Tibbert van den Eynde,
- Melanie M. van der Klauw,
- Diana van 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,
- Marco Medici
Affiliations
- Rosalie B. T. M. Sterenborg
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- Inga Steinbrenner
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg
- Yong Li
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg
- Melissa N. Bujnis
- The University of Utah
- Tatsuhiko Naito
- Department of Statistical Genetics, Osaka University Graduate School of Medicine
- Eirini Marouli
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
- Tessel E. Galesloot
- Department for Health Evidence, Radboud University Medical Center
- Oladapo Babajide
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
- Laura Andreasen
- Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital - Rigshospitalet
- Arne Astrup
- Department of Obesity and Nutritional Sciences, The Novo Nordisk Foundation
- Bjørn Olav Åsvold
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology
- Stefania Bandinelli
- Geriatric Unit, Azienda Sanitaria Toscana Centro
- Marian Beekman
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center
- John P. Beilby
- School of Biomedical Sciences, The University of Western Australia
- Jette Bork-Jensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Thibaud Boutin
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital
- Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Suzanne J. Brown
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- Ben Brumpton
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology
- Purdey J. Campbell
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- Anne R. Cappola
- Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania
- Graziano Ceresini
- Oncological Endocrinology, University of Parma
- Layal Chaker
- Department of Internal Medicine, Erasmus Medical Center
- Daniel I. Chasman
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Maria Pina Concas
- Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
- Rodrigo Coutinho de Almeida
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center
- Simone M. Cross
- QIMR Berghofer Medical Research Institute
- Francesco Cucca
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
- Ian J. Deary
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Alisa Devedzic Kjaergaard
- Steno Diabetes Center Aarhus, Aarhus University Hospital
- Justin B. Echouffo Tcheugui
- Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins School of Medicine
- Christina Ellervik
- Harvard Medical School
- Johan G. Eriksson
- Department of General Practice and Primary health Care, University of Helsinki
- Luigi Ferrucci
- Longitudinal Study Section, National Institute on Aging
- Jan Freudenberg
- Regeneron Pharmaceuticals, Inc., Tarrytown
- GHS DiscovEHR
- Regeneron Genetics Center
- Christian Fuchsberger
- Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
- Christian Gieger
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München
- Franco Giulianini
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Martin Gögele
- Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
- Sarah E. Graham
- Department of Internal Medicine, Cardiology, University of Michigan
- Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Ivana Gunjača
- Department of Medical Biology, University of Split, School of Medicine
- Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Barbara N. Harding
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Sarah E. Harris
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Stig Haunsø
- Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital - Rigshospitalet
- Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital
- Jennie Hui
- Pathwest Laboratory Medicine WA
- Till Ittermann
- Institute for Community Medicine, University Medicine Greifswald
- J. Wouter Jukema
- Department of Cardiology, Leiden University Medical Center
- Eero Kajantie
- Finnish Institute for Health and Welfare, Population Health Unit, Helsinki and Oulu
- Jørgen K. Kanters
- Department of Biomedical Sciences, University of Copenhagen
- Line L. Kårhus
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital
- Lambertus A. L. M. Kiemeney
- Department for Health Evidence, Radboud University Medical Center
- Margreet Kloppenburg
- Departments of Rheumatology and Clinical Epidemiology, Leiden University Medical Center
- Brigitte Kühnel
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München
- Jari Lahti
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- Claudia Langenberg
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
- Bruno Lapauw
- Department of Endocrinology, Ghent University Hospital, C. Heymanslaan 10
- Graham Leese
- NHS Tayside
- Shuo Li
- Department of Biostatistics, Boston University
- David C. M. Liewald
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Allan Linneberg
- Center of Physiological Research, University of California San Francisco
- Jesus V. T. Lominchar
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Jian’an Luan
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
- Nicholas G. Martin
- QIMR Berghofer Medical Research Institute
- Antonela Matana
- Department of Medical Biology, University of Split, School of Medicine
- Marcel E. Meima
- Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center
- Thomas Meitinger
- Institute for Human Genetics, Technical University of Munich
- Ingrid Meulenbelt
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center
- Braxton D. Mitchell
- University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition
- Line T. Møllehave
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital
- Samia Mora
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Silvia Naitza
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
- Matthias Nauck
- DZHK (German Center for Cardiovascular Research), partner site Greifswald
- Romana T. Netea-Maier
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Casia Nursyifa
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine
- Stefano Onano
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
- Areti Papadopoulou
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
- Colin N. A. Palmer
- Division of Population Health Genomics, School of Medicine, University of Dundee
- Cristian Pattaro
- Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
- Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- Maik Pietzner
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
- Ozren Polašek
- Department of Public Health, University of Split, School of Medicine
- Peter P. Pramstaller
- Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research
- Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Ante Punda
- Department of Nuclear Medicine, University Hospital Split
- Debashree Ray
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health
- Paul Redmond
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- J. Brent Richards
- Lady Davis Institute, Jewish General Hospital, Montreal
- Paul M. Ridker
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Tom C. Russ
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Kathleen A. Ryan
- University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition
- Morten Salling Olesen
- Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital - Rigshospitalet
- Ulla T. Schultheiss
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg
- Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health
- Moneeza K. Siddiqui
- Wolfson Institute of Population Health, Queen Mary University of London
- Carlo Sidore
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
- P. Eline Slagboom
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center
- Thorkild I. A. Sørensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Enrique Soto-Pedre
- Division of Population Health Genomics, School of Medicine, University of Dundee
- Tim D. Spector
- The Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus
- Beatrice Spedicati
- Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
- Sundararajan Srinivasan
- Division of Population Health Genomics, School of Medicine, University of Dundee
- John M. Starr
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh
- David J. Stott
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow
- Toshiko Tanaka
- Longitudinal Study Section, National Institute on Aging
- Vesela Torlak
- Department of Nuclear Medicine, University Hospital Split
- Stella Trompet
- Department of Cardiology, Leiden University Medical Center
- Johanna Tuhkanen
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- André G. Uitterlinden
- Department of Internal Medicine, Erasmus Medical Center
- Erik B. van den Akker
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center
- Tibbert van den Eynde
- Precision Healthcare University Research Institute, Queen Mary University of London
- Melanie M. van der Klauw
- Department of Endocrinology, University of Groningen, University Medical Center Groningen
- Diana van Heemst
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Charlotte Verroken
- Department of Endocrinology, Ghent University Hospital, C. Heymanslaan 10
- W. Edward Visser
- Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center
- Dina Vojinovic
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center
- Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald
- Melanie Waldenberger
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München
- John P. Walsh
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital
- Nicholas J. Wareham
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine
- Stefan Weiss
- DZHK (German Center for Cardiovascular Research), partner site Greifswald
- Cristen J. Willer
- Department of Internal Medicine, Cardiology, University of Michigan
- Scott G. Wilson
- School of Biomedical Sciences, The University of Western Australia
- Bruce H. R. Wolffenbuttel
- Department of Endocrinology, University of Groningen, University Medical Center Groningen
- Hanneke J. C. M. Wouters
- Department of Endocrinology, University of Groningen, University Medical Center Groningen
- Margaret J. Wright
- Queensland Brain Institute, University of Queensland
- Qiong Yang
- Department of Biostatistics, Boston University
- Tatijana Zemunik
- Department of Medical Biology, University of Split, School of Medicine
- Wei Zhou
- Analytic and Translational Genetics Unit, Massachusetts General Hospital
- Gu Zhu
- QIMR Berghofer Medical Research Institute
- Sebastian Zöllner
- Department of Biostatistics, University of Michigan
- Johannes W. A. Smit
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- Robin P. Peeters
- Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center
- Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg
- Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald
- Marco Medici
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- DOI
- https://doi.org/10.1038/s41467-024-44701-9
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
