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Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Listed:
  • Alexander Teumer

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Layal Chaker

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center
    Erasmus Medical Center)

  • Stefan Groeneweg

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center)

  • Yong Li

    (Faculty of Medicine and Medical Center—University of Freiburg)

  • Celia Di Munno

    (Erasmus MC Academic Center for Thyroid Diseases
    University of Sannio)

  • Caterina Barbieri

    (San Raffaele Scientific Institute)

  • Ulla T. Schultheiss

    (Faculty of Medicine and Medical Center—University of Freiburg)

  • Michela Traglia

    (San Raffaele Scientific Institute)

  • Tarunveer S. Ahluwalia

    (Steno Diabetes Center Copenhagen
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Masato Akiyama

    (RIKEN Center for Integrative Medical Sciences)

  • Emil Vincent R. Appel

    (Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Dan E. Arking

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine)

  • Alice Arnold

    (University of Washington)

  • Arne Astrup

    (University of Copenhagen)

  • Marian Beekman

    (Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center)

  • John P. Beilby

    (Pathwest Laboratory Medicine WA
    University of Western Australia)

  • Sofie Bekaert

    (Ghent University Hospital)

  • Eric Boerwinkle

    (University of Texas Health Science Center)

  • Suzanne J. Brown

    (Sir Charles Gairdner Hospital)

  • Marc De Buyzere

    (Ghent University Hospital)

  • Purdey J. Campbell

    (Sir Charles Gairdner Hospital)

  • Graziano Ceresini

    (Department of Medicine and Surgery, University of Parma, University Hospital of Parma)

  • Charlotte Cerqueira

    (The Capital Region)

  • Francesco Cucca

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato
    Università degli Studi di Sassari)

  • Ian J. Deary

    (University of Edinburgh
    University of Edinburgh)

  • Joris Deelen

    (Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center
    Max Planck Institute for Biology of Ageing)

  • Kai-Uwe Eckardt

    (University of Erlangen-Nürnberg
    Charité – Universitätsmedizin Berlin)

  • Arif B. Ekici

    (Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Johan G. Eriksson

    (University of Helsinki and Helsinki University Hospital
    Folkhälsan Research Center
    National Institute for Health and Welfare)

  • Luigi Ferrrucci

    (National Institute on Aging)

  • Tom Fiers

    (Ghent University Hospital)

  • Edoardo Fiorillo

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato)

  • Ian Ford

    (University of Glasgow)

  • Caroline S. Fox

    (National Heart, Lung, and Blood Institute’s Framingham Heart Study and the Center for Population Studies
    Brigham and Women’s Hospital and Harvard Medical School)

  • Christian Fuchsberger

    (Affiliated Institute of the University of Lubeck)

  • Tessel E. Galesloot

    (Radboud Institute for Health Sciences)

  • Christian Gieger

    (German Research Center for Environmental Health
    German Research Centre for Environmental Health)

  • Martin Gögele

    (Affiliated Institute of the University of Lubeck)

  • Alessandro De Grandi

    (Affiliated Institute of the University of Lubeck)

  • Niels Grarup

    (Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Karin Halina Greiser

    (German Research Centre Division of Cancer Epidemiology)

  • Kadri Haljas

    (University of Helsinki)

  • Torben Hansen

    (Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Sarah E. Harris

    (University of Edinburgh
    University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine)

  • Diana Heemst

    (Leiden University Medical Center, Geriatrics and Gerontology)

  • Martin Heijer

    (Vrije Universiteit Medisch Centrum)

  • Andrew A. Hicks

    (Affiliated Institute of the University of Lubeck)

  • Wouter Hollander

    (Leiden University Medical Center)

  • Georg Homuth

    (Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald)

  • Jennie Hui

    (Pathwest Laboratory Medicine WA
    University of Western Australia)

  • M. Arfan Ikram

    (Erasmus Medical Center)

  • Till Ittermann

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Richard A. Jensen

    (University of Washington)

  • Jiaojiao Jing

    (Faculty of Medicine and Medical Center—University of Freiburg
    Faculty of Biology, University of Freiburg)

  • J. Wouter Jukema

    (Leiden University Medical Center
    Einthoven Laboratory for Experimental Vascular Medicine, LUMC)

  • Eero Kajantie

    (National Institute for Health and Welfare
    Children’s Hospital, Helsinki University Hospital and University of Helsinki
    MRC Oulu, Oulu University Hospital and University of Oulu)

  • Yoichiro Kamatani

    (RIKEN Center for Integrative Medical Sciences
    Center for Genomic Medicine, Kyoto University Graduate School of Medicine)

  • Elisa Kasbohm

    (University Medicine Greifswald
    Institute of Epidemiology, Friedrich-Loeffler-Institut (FLI), Federal Research Institute for Animal Health)

  • Jean-Marc Kaufman

    (Ghent University Hospital)

  • Lambertus A. Kiemeney

    (Radboud Institute for Health Sciences)

  • Margreet Kloppenburg

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Florian Kronenberg

    (Medical University of Innsbruck)

  • Michiaki Kubo

    (RIKEN Center for Integrative Medical Sciences)

  • Jari Lahti

    (University of Helsinki)

  • Bruno Lapauw

    (Ghent University Hospital)

  • Shuo Li

    (Boston University)

  • David C. M. Liewald

    (University of Edinburgh
    University of Edinburgh)

  • Ee Mun Lim

    (Pathwest Laboratory Medicine WA
    Sir Charles Gairdner Hospital)

  • Allan Linneberg

    (The Capital Region
    Rigshospitalet)

  • Michela Marina

    (Department of Medicine and Surgery, University of Parma, University Hospital of Parma)

  • Deborah Mascalzoni

    (Affiliated Institute of the University of Lubeck)

  • Koichi Matsuda

    (The University of Tokyo)

  • Daniel Medenwald

    (Martin-Luther-University Halle-Wittenberg)

  • Christa Meisinger

    (German Research Center for Environmental Health
    Ludwig-Maximilians-Universität München, at UNIKA-T Augsburg)

  • Ingrid Meulenbelt

    (Leiden University Medical Center)

  • Tim De Meyer

    (Ghent University)

  • Henriette E. Meyer zu Schwabedissen

    (University of Basel)

  • Rafael Mikolajczyk

    (Martin-Luther-University Halle-Wittenberg)

  • Matthijs Moed

    (Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center)

  • Romana T. Netea-Maier

    (Radboud University Medical Center)

  • Ilja M. Nolte

    (University of Groningen, University Medical Center Groningen)

  • Yukinori Okada

    (RIKEN Center for Integrative Medical Sciences
    Osaka University Graduate School of Medicine
    Osaka University)

  • Mauro Pala

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato)

  • Cristian Pattaro

    (Affiliated Institute of the University of Lubeck)

  • Oluf Pedersen

    (Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Astrid Petersmann

    (University Medicine Greifswald)

  • Eleonora Porcu

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato
    University of Lausanne, and Swiss Institute of Bioinformatics)

  • Iris Postmus

    (Section of Gerontology and Geriatrics, Leiden University Medical Center)

  • Peter P. Pramstaller

    (Affiliated Institute of the University of Lubeck)

  • Bruce M. Psaty

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Yolande F. M. Ramos

    (Leiden University Medical Center)

  • Rajesh Rawal

    (German Research Center for Environmental Health)

  • Paul Redmond

    (University of Edinburgh)

  • J. Brent Richards

    (Jewish General Hospital
    King’s College London, St. Thomas’ Campus)

  • Ernst R. Rietzschel

    (Ghent University Hospital
    Ghent University)

  • Fernando Rivadeneira

    (Erasmus Medical Center
    Erasmus Medical Center)

  • Greet Roef

    (Ghent University Hospital)

  • Jerome I. Rotter

    (LABioMed at Harbor-UCLA Medical Center)

  • Cinzia F. Sala

    (San Raffaele Scientific Institute)

  • David Schlessinger

    (National Institute on Aging, National Institutes of Health)

  • Elizabeth Selvin

    (Johns Hopkins Bloomberg School of Public Health)

  • P. Eline Slagboom

    (Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center)

  • Nicole Soranzo

    (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton)

  • Thorkild I. A. Sørensen

    (Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
    University of Copenhagen)

  • Timothy D. Spector

    (King’s College London, St. Thomas’ Campus)

  • John M. Starr

    (University of Edinburgh
    University of Edinburgh)

  • David J. Stott

    (Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow)

  • Youri Taes

    (AZ Sint Jan Brugge)

  • Daniel Taliun

    (Affiliated Institute of the University of Lubeck)

  • Toshiko Tanaka

    (National Institute on Aging)

  • Betina Thuesen

    (The Capital Region)

  • Daniel Tiller

    (Ludwig-Maximilians-Universität München, at UNIKA-T Augsburg)

  • Daniela Toniolo

    (San Raffaele Scientific Institute)

  • Andre G. Uitterlinden

    (Erasmus Medical Center
    Erasmus Medical Center)

  • W. Edward Visser

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center)

  • John P. Walsh

    (Sir Charles Gairdner Hospital
    University of Western Australia)

  • Scott G. Wilson

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

  • Bruce H. R. Wolffenbuttel

    (University of Groningen, University Medical Center Groningen)

  • Qiong Yang

    (Boston University)

  • Hou-Feng Zheng

    (Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University and Westlake Institute for Advanced Study
    Institute of Aging Research and the Affiliated Hospital, School of Medicine, Hangzhou Normal University)

  • Anne Cappola

    (University of Pennsylvania School of Medicine)

  • Robin P. Peeters

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center)

  • Silvia Naitza

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato)

  • Henry Völzke

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Serena Sanna

    (Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato
    University of Groningen, University Medical Center Groningen)

  • Anna Köttgen

    (Faculty of Medicine and Medical Center—University of Freiburg
    Johns Hopkins Bloomberg School of Public Health)

  • Theo J. Visser

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center)

  • Marco Medici

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center
    Erasmus Medical Center)

Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Suggested Citation

  • Alexander Teumer & Layal Chaker & Stefan Groeneweg & Yong Li & Celia Di Munno & Caterina Barbieri & Ulla T. Schultheiss & Michela Traglia & Tarunveer S. Ahluwalia & Masato Akiyama & Emil Vincent R. Ap, 2018. "Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06356-1
    DOI: 10.1038/s41467-018-06356-1
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    Cited by:

    1. 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.
    2. Yuandan Wei & Jianxin Zhen & Liang Hu & Yuqin Gu & Yanhong Liu & Xinxin Guo & Zijing Yang & Hao Zheng & Shiyao Cheng & Fengxiang Wei & Likuan Xiong & Siyang Liu, 2024. "Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Hanneke J C M Wouters & Sandra N Slagter & Anneke C Muller Kobold & Melanie M van der Klauw & Bruce H R Wolffenbuttel, 2020. "Epidemiology of thyroid disorders in the Lifelines Cohort Study (the Netherlands)," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-17, November.
    4. Alexander T. Williams & Jing Chen & Kayesha Coley & Chiara Batini & Abril Izquierdo & Richard Packer & Erik Abner & Stavroula Kanoni & David J. Shepherd & Robert C. Free & Edward J. Hollox & Nigel J. , 2023. "Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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