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

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. Appel, Dan E. Arking, Alice Arnold, Arne Astrup, Marian Beekman, John P. Beilby, Sofie Bekaert, Eric Boerwinkle, Suzanne J. Brown, Marc De Buyzere, Purdey J. Campbell, Graziano Ceresini, Charlotte Cerqueira, Francesco Cucca, Ian J. Deary, Joris Deelen, Kai-Uwe Eckardt, Arif B. Ekici, Johan G. Eriksson, Luigi Ferrrucci, Tom Fiers, Edoardo Fiorillo, Ian Ford, Caroline S. Fox, Christian Fuchsberger, Tessel E. Galesloot, Christian Gieger, Martin Gögele, Alessandro De Grandi, Niels Grarup, Karin Halina Greiser, Kadri Haljas, Torben Hansen, Sarah E. Harris, Diana Heemst, Martin Heijer, Andrew A. Hicks, Wouter Hollander, Georg Homuth, Jennie Hui, M. Arfan Ikram, Till Ittermann, Richard A. Jensen, Jiaojiao Jing, J. Wouter Jukema, Eero Kajantie, Yoichiro Kamatani, Elisa Kasbohm, Jean-Marc Kaufman, Lambertus A. Kiemeney, Margreet Kloppenburg, Florian Kronenberg, Michiaki Kubo, Jari Lahti, Bruno Lapauw, Shuo Li, David C. M. Liewald, Ee Mun Lim, Allan Linneberg, Michela Marina, Deborah Mascalzoni, Koichi Matsuda, Daniel Medenwald, Christa Meisinger, Ingrid Meulenbelt, Tim De Meyer, Henriette E. Meyer zu Schwabedissen, Rafael Mikolajczyk, Matthijs Moed, Romana T. Netea-Maier, Ilja M. Nolte, Yukinori Okada, Mauro Pala, Cristian Pattaro, Oluf Pedersen, Astrid Petersmann, Eleonora Porcu, Iris Postmus, Peter P. Pramstaller, Bruce M. Psaty, Yolande F. M. Ramos, Rajesh Rawal, Paul Redmond, J. Brent Richards, Ernst R. Rietzschel, Fernando Rivadeneira, Greet Roef, Jerome I. Rotter, Cinzia F. Sala, David Schlessinger, Elizabeth Selvin, P. Eline Slagboom, Nicole Soranzo, Thorkild I. A. Sørensen, Timothy D. Spector, John M. Starr, David J. Stott, Youri Taes, Daniel Taliun, Toshiko Tanaka, Betina Thuesen, Daniel Tiller, Daniela Toniolo, Andre G. Uitterlinden, W. Edward Visser, John P. Walsh, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Qiong Yang, Hou-Feng Zheng, Anne Cappola, Robin P. Peeters, Silvia Naitza, Henry Völzke, Serena Sanna, Anna Köttgen, Theo J. Visser and Marco Medici
Additional contact information
Alexander Teumer: University Medicine Greifswald
Layal Chaker: Erasmus MC Academic Center for Thyroid Diseases
Stefan Groeneweg: Erasmus MC Academic Center for Thyroid Diseases
Yong Li: Faculty of Medicine and Medical Center—University of Freiburg
Celia Di Munno: Erasmus MC Academic Center for Thyroid Diseases
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
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
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
Ian J. Deary: University of Edinburgh
Joris Deelen: Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center
Kai-Uwe Eckardt: University of Erlangen-Nürnberg
Arif B. Ekici: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Johan G. Eriksson: University of Helsinki and Helsinki University Hospital
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
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
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
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
M. Arfan Ikram: Erasmus Medical Center
Till Ittermann: University Medicine Greifswald
Richard A. Jensen: University of Washington
Jiaojiao Jing: Faculty of Medicine and Medical Center—University of Freiburg
J. Wouter Jukema: Leiden University Medical Center
Eero Kajantie: National Institute for Health and Welfare
Yoichiro Kamatani: RIKEN Center for Integrative Medical Sciences
Elisa Kasbohm: University Medicine Greifswald
Jean-Marc Kaufman: Ghent University Hospital
Lambertus A. Kiemeney: Radboud Institute for Health Sciences
Margreet Kloppenburg: 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
Ee Mun Lim: Pathwest Laboratory Medicine WA
Allan Linneberg: The Capital Region
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
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
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
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
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
Ernst R. Rietzschel: Ghent University Hospital
Fernando Rivadeneira: 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
Timothy D. Spector: King’s College London, St. Thomas’ Campus
John M. Starr: 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
W. Edward Visser: Erasmus MC Academic Center for Thyroid Diseases
John P. Walsh: Sir Charles Gairdner Hospital
Scott G. Wilson: Sir Charles Gairdner Hospital
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
Anne Cappola: University of Pennsylvania School of Medicine
Robin P. Peeters: Erasmus MC Academic Center for Thyroid Diseases
Silvia Naitza: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato
Henry Völzke: University Medicine Greifswald
Serena Sanna: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato
Anna Köttgen: Faculty of Medicine and Medical Center—University of Freiburg
Theo J. Visser: Erasmus MC Academic Center for Thyroid Diseases
Marco Medici: Erasmus MC Academic Center for Thyroid Diseases

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06356-1

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