Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
38291025
TITLE
Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.
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.
© 2024. The Author(s).
DATE PUBLISHED
2024 Jan 30
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2023/03/07
accepted 2023/12/29
medline 2024/02/01 06:43
pubmed 2024/01/31 00:42
entrez 2024/01/30 23:14
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Sterenborg RBTM Sterenborg Rosalie B T M RBTM Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Steinbrenner I Steinbrenner Inga I Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
Li Y Li Yong Y Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
Bujnis MN Bujnis Melissa N MN The University of Utah, Salt Lake City, UT, USA.
Naito T Naito Tatsuhiko T Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Marouli E Marouli Eirini E Digital Environment Research Institute, Queen Mary University of London, London, UK.
Galesloot TE Galesloot Tessel E TE Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
Babajide O Babajide Oladapo O William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Andreasen L Andreasen Laura L Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Astrup A Astrup Arne A Department of Obesity and Nutritional Sciences, The Novo Nordisk Foundation, Hellerup, Denmark.
Åsvold BO Åsvold Bjørn Olav BO Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Bandinelli S Bandinelli Stefania S Geriatric Unit, Azienda Sanitaria Toscana Centro, Florence, Italy.
Beekman M Beekman Marian M Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Beilby JP Beilby John P JP School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
Bork-Jensen J Bork-Jensen Jette J Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Boutin T Boutin Thibaud T MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
Brody JA Brody Jennifer A JA Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Brown SJ Brown Suzanne J SJ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Brumpton B Brumpton Ben B HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, 7600, Norway.
Campbell PJ Campbell Purdey J PJ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Cappola AR Cappola Anne R AR Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania, Philadelphia, PA, USA.
Ceresini G Ceresini Graziano G Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Chaker L Chaker Layal L Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Chasman DI Chasman Daniel I DI Harvard Medical School, Boston, USA.
Concas MP Concas Maria Pina MP Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
Coutinho de Almeida R Coutinho de Almeida Rodrigo R Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Cross SM Cross Simone M SM QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Cucca F Cucca Francesco F Università di Sassari, Dipartimento di Scienze Biomediche, V.le San Pietro, 07100, Sassari (SS), Italy.
Deary IJ Deary Ian J IJ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, EH8 9JZ, Edinburgh, United Kingdom.
Kjaergaard AD Kjaergaard Alisa Devedzic AD Steno Diabetes Center Aarhus, Aarhus University Hospital, Palle Juul-Jensens Blvd. 11, Entrance A, 8200, Aarhus, Denmark.
Echouffo Tcheugui JB Echouffo Tcheugui Justin B JB Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Ellervik C Ellervik Christina C Department of Clinical Biochemistry, Zealand University Hospital, Køge, Denmark.
Eriksson JG Eriksson Johan G JG National University Singapore, Yong Loo Lin School of Medicine, Department of Obstetrics and Gynecology, Singapore, Singapore.
Ferrucci L Ferrucci Luigi L Longitudinal Study Section, National Institute on Aging, Baltimore, MD, USA.
Freudenberg J Freudenberg Jan J Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
GHS DiscovEHR
Regeneron Genetics Center
Fuchsberger C Fuchsberger Christian C Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research, Bolzano, Italy.
Gieger C Gieger Christian C Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
Giulianini F Giulianini Franco F Division of Preventive Medicine, Brigham and Women's Hospital, Boston, USA.
Gögele M Gögele Martin M Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research, Bolzano, Italy.
Graham SE Graham Sarah E SE Department of Internal Medicine, Cardiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Grarup N Grarup Niels N Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Gunjača I Gunjača Ivana I Department of Medical Biology, University of Split, School of Medicine, Split, Croatia.
Hansen T Hansen Torben T Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Harding BN Harding Barbara N BN Barcelona Institute for Global Health, Barcelona, Spain.
Harris SE Harris Sarah E SE Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, EH8 9JZ, Edinburgh, United Kingdom.
Haunsø S Haunsø Stig S Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Hayward C Hayward Caroline C MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
Hui J Hui Jennie J School of Population and Global Health, The University of Western Australia, Crawley, WA, 6009, Australia.
Ittermann T Ittermann Till T DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Jukema JW Jukema J Wouter JW Netherlands Heart Institute, Utrecht, the Netherlands.
Kajantie E Kajantie Eero E Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Kanters JK Kanters Jørgen K JK Center of Physiological Research, University of California San Francisco, San Francisco, USA.
Kårhus LL Kårhus Line L LL Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Kiemeney LALM Kiemeney Lambertus A L M LALM Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
Kloppenburg M Kloppenburg Margreet M Departments of Rheumatology and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Kühnel B Kühnel Brigitte B Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
Lahti J Lahti Jari J Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Langenberg C Langenberg Claudia C Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
Lapauw B Lapauw Bruno B Department of Endocrinology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.
Leese G Leese Graham G NHS Tayside, Scotland, Dundee, UK.
Li S Li Shuo S Department of Biostatistics, Boston University, Boston, MA, USA.
Liewald DCM Liewald David C M DCM Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, EH8 9JZ, Edinburgh, United Kingdom.
Linneberg A Linneberg Allan A Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Lominchar JVT Lominchar Jesus V T JVT Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Luan J Luan Jian'an J MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Matana A Matana Antonela A Department of Medical Biology, University of Split, School of Medicine, Split, Croatia.
Meima ME Meima Marcel E ME Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Meitinger T Meitinger Thomas T Institute for Human Genetics, Technical University of Munich, Munich, Germany.
Meulenbelt I Meulenbelt Ingrid I Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Mitchell BD Mitchell Braxton D BD Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, 21201, USA.
Møllehave LT Møllehave Line T LT Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Mora S Mora Samia S Harvard Medical School, Boston, USA.
Naitza S Naitza Silvia S Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042, Monserrato (CA), Italy.
Nauck M Nauck Matthias M Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Netea-Maier RT Netea-Maier Romana T RT Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
Noordam R Noordam Raymond R Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Nursyifa C Nursyifa Casia C Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Okada Y Okada Yukinori Y Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Japan.
Onano S Onano Stefano S Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042, Monserrato (CA), Italy.
Papadopoulou A Papadopoulou Areti A William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Palmer CNA Palmer Colin N A CNA Division of Population Health Genomics, School of Medicine, University of Dundee, DD19SY, Dundee, UK.
Pattaro C Pattaro Cristian C Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research, Bolzano, Italy.
Pedersen O Pedersen Oluf O Center for Clinical Metabolic Research, Herlev-Gentofte University Hospital, Copenhagen, Denmark.
Peters A Peters Annette A Chair of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.
Pietzner M Pietzner Maik M Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
Polašek O Polašek Ozren O Algebra University College, Zagreb, Croatia.
Pramstaller PP Pramstaller Peter P PP Institute for Biomedicine (affiliated with the University of Lübeck), Eurac Research, Bolzano, Italy.
Psaty BM Psaty Bruce M BM Departments of Epidemiology and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
Punda A Punda Ante A Department of Nuclear Medicine, University Hospital Split, Split, Croatia.
Ray D Ray Debashree D Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
Redmond P Redmond Paul P Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, EH8 9JZ, Edinburgh, United Kingdom.
Richards JB Richards J Brent JB Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada.
Ridker PM Ridker Paul M PM Harvard Medical School, Boston, USA.
Russ TC Russ Tom C TC Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
Ryan KA Ryan Kathleen A KA University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition, Baltimore, USA.
Olesen MS Olesen Morten Salling MS Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Schultheiss UT Schultheiss Ulla T UT Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
Selvin E Selvin Elizabeth E Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
Siddiqui MK Siddiqui Moneeza K MK Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
Sidore C Sidore Carlo C Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042, Monserrato (CA), Italy.
Slagboom PE Slagboom P Eline PE Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Sørensen TIA Sørensen Thorkild I A TIA Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Soto-Pedre E Soto-Pedre Enrique E Division of Population Health Genomics, School of Medicine, University of Dundee, DD19SY, Dundee, UK.
Spector TD Spector Tim D TD The Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Campus, Lambeth Palace Road, London, SE1 7EH, UK.
Spedicati B Spedicati Beatrice B Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Srinivasan S Srinivasan Sundararajan S Division of Population Health Genomics, School of Medicine, University of Dundee, DD19SY, Dundee, UK.
Starr JM Starr John M JM Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
Stott DJ Stott David J DJ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Tanaka T Tanaka Toshiko T Longitudinal Study Section, National Institute on Aging, Baltimore, MD, USA.
Torlak V Torlak Vesela V Department of Nuclear Medicine, University Hospital Split, Split, Croatia.
Trompet S Trompet Stella S Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Tuhkanen J Tuhkanen Johanna J Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Uitterlinden AG Uitterlinden André G AG Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
van den Akker EB van den Akker Erik B EB Department of Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands.
van den Eynde T van den Eynde Tibbert T Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
van der Klauw MM van der Klauw Melanie M MM Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
van Heemst D van Heemst Diana D Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Verroken C Verroken Charlotte C Department of Endocrinology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.
Visser WE Visser W Edward WE Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Vojinovic D Vojinovic Dina D Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Völzke H Völzke Henry H DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Waldenberger M Waldenberger Melanie M Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
Walsh JP Walsh John P JP Medical School, The University of Western Australia, Crawley, WA, 6009, Australia.
Wareham NJ Wareham Nicholas J NJ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
Weiss S Weiss Stefan S Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Willer CJ Willer Cristen J CJ Department of Internal Medicine, Cardiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Wilson SG Wilson Scott G SG The Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Campus, Lambeth Palace Road, London, SE1 7EH, UK.
Wolffenbuttel BHR Wolffenbuttel Bruce H R BHR Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Wouters HJCM Wouters Hanneke J C M HJCM Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Wright MJ Wright Margaret J MJ Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
Yang Q Yang Qiong Q Department of Biostatistics, Boston University, Boston, MA, USA.
Zemunik T Zemunik Tatijana T Department of Nuclear Medicine, University Hospital Split, Split, Croatia.
Zhou W Zhou Wei W Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Zhu G Zhu Gu G QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Zöllner S Zöllner Sebastian S Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
Smit JWA Smit Johannes W A JWA Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
Peeters RP Peeters Robin P RP Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Köttgen A Köttgen Anna A CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Teumer A Teumer Alexander A Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland. ateumer@uni-greifswald.de.
Medici M Medici Marco M Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. m.medici@erasmusmc.nl.
INVESTIGATORS
JOURNAL
VOLUME: 15
ISSUE: 1
TITLE: Nature communications
ISOABBREVIATION: Nat Commun
YEAR: 2024
MONTH: Jan
DAY: 30
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 2041-1723
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Commun
COUNTRY: England
ISSNLINKING: 2041-1723
NLMUNIQUEID: 101528555
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Meta-Analysis
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
R35 GM118335 NIGMS NIH HHS United States
T32 DK110966 NIDDK NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Humans
Thyroid Gland metabolism
Thyroxine metabolism
Genome-Wide Association Study metabolism
Triiodothyronine metabolism
Thyrotropin metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
Q51BO43MG4 Thyroxine
06LU7C9H1V Triiodothyronine
9002-71-5 Thyrotropin
OTHER ID's
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