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

ORCID
0000-0002-8309-094X
Zugehörigkeit
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. ateumer@uni-greifswald.de.
Teumer, Alexander;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Chaker, Layal;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Groeneweg, Stefan;
Zugehörigkeit
Department of Biometry, Epidemiology and Medical Bioinformatics, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
Li, Yong;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Di Munno, Celia;
Zugehörigkeit
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Barbieri, Caterina;
Zugehörigkeit
Department of Biometry, Epidemiology and Medical Bioinformatics, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
Schultheiss, Ulla T;
Zugehörigkeit
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Traglia, Michela;
ORCID
0000-0002-7464-3354
Zugehörigkeit
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
Ahluwalia, Tarunveer S;
Zugehörigkeit
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Akiyama, Masato;
ORCID
0000-0001-7704-6611
Zugehörigkeit
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Appel, Emil Vincent R;
Zugehörigkeit
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Arking, Dan E;
Zugehörigkeit
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Arnold, Alice;
ORCID
0000-0001-8968-8996
Zugehörigkeit
Department of Nutrition, Exercise, and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Astrup, Arne;
ORCID
0000-0003-0585-6206
Zugehörigkeit
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Beekman, Marian;
ORCID
0000-0002-4915-2254
Zugehörigkeit
Pathwest Laboratory Medicine WA, Nedlands, WA, 6009, Australia.
Beilby, John P;
Zugehörigkeit
Bimetra, Clinical Research Center Ghent, Ghent University Hospital, Ghent, Belgium.
Bekaert, Sofie;
Zugehörigkeit
Human Genetics Center, University of Texas Health Science Center, 1200 Pressler Street, Houston, TX, 77030, USA.
Boerwinkle, Eric;
Zugehörigkeit
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Brown, Suzanne J;
Zugehörigkeit
Department of Cardiology, Ghent University Hospital, Ghent, Belgium.
De Buyzere, Marc;
Zugehörigkeit
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Campbell, Purdey J;
Zugehörigkeit
Department of Medicine and Surgery, University of Parma, University Hospital of Parma, Parma, Italy.
Ceresini, Graziano;
Zugehörigkeit
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
Cerqueira, Charlotte;
Zugehörigkeit
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Cucca, Francesco;
Zugehörigkeit
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Deary, Ian J;
Zugehörigkeit
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Deelen, Joris;
Zugehörigkeit
Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany.
Eckardt, Kai-Uwe;
ORCID
0000-0001-6099-7066
Zugehörigkeit
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Ekici, Arif B;
Zugehörigkeit
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Eriksson, Johan G;
Zugehörigkeit
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
Ferrrucci, Luigi;
Zugehörigkeit
Department of Clinical Chemistry, Ghent University Hospital, Ghent, Belgium.
Fiers, Tom;
Zugehörigkeit
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Fiorillo, Edoardo;
Zugehörigkeit
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
Ford, Ian;
Zugehörigkeit
National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA, USA.
Fox, Caroline S;
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Fuchsberger, Christian;
Zugehörigkeit
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Galesloot, Tessel E;
Zugehörigkeit
Helmholtz Zentrum München, Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany.
Gieger, Christian;
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Gögele, Martin;
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
De Grandi, Alessandro;
ORCID
0000-0001-5526-1070
Zugehörigkeit
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Grarup, Niels;
Zugehörigkeit
German Research Centre Division of Cancer Epidemiology, Heidelberg, Germany.
Greiser, Karin Halina;
Zugehörigkeit
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Haljas, Kadri;
ORCID
0000-0001-8748-3831
Zugehörigkeit
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Hansen, Torben;
Zugehörigkeit
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Harris, Sarah E;
Zugehörigkeit
Leiden University Medical Center, Geriatrics and Gerontology, Leiden, The Netherlands.
van Heemst, Diana;
Zugehörigkeit
Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
den Heijer, Martin;
ORCID
0000-0001-6320-0411
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Hicks, Andrew A;
Zugehörigkeit
Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
den Hollander, Wouter;
Zugehörigkeit
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Homuth, Georg;
Zugehörigkeit
Pathwest Laboratory Medicine WA, Nedlands, WA, 6009, Australia.
Hui, Jennie;
ORCID
0000-0003-0372-8585
Zugehörigkeit
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Ikram, M Arfan;
Zugehörigkeit
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Ittermann, Till;
Zugehörigkeit
Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
Jensen, Richard A;
Zugehörigkeit
Department of Biometry, Epidemiology and Medical Bioinformatics, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
Jing, Jiaojiao;
ORCID
0000-0002-3246-8359
Zugehörigkeit
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Jukema, J Wouter;
Zugehörigkeit
National Institute for Health and Welfare, Helsinki, Finland.
Kajantie, Eero;
ORCID
0000-0001-8748-5597
Zugehörigkeit
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Kamatani, Yoichiro;
GND
1148758380
Zugehörigkeit
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Kasbohm, Elisa;
Zugehörigkeit
Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
Kaufman, Jean-Marc;
Zugehörigkeit
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Kiemeney, Lambertus A;
Zugehörigkeit
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Kloppenburg, Margreet;
ORCID
0000-0003-2229-1120
Zugehörigkeit
Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Kronenberg, Florian;
Zugehörigkeit
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Kubo, Michiaki;
ORCID
0000-0002-4310-5297
Zugehörigkeit
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Lahti, Jari;
Zugehörigkeit
Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
Lapauw, Bruno;
ORCID
0000-0003-2331-2448
Zugehörigkeit
Department of Biostatistics, Boston University, Boston, MA, USA.
Li, Shuo;
ORCID
0000-0002-0544-7368
Zugehörigkeit
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Liewald, David C M;
Zugehörigkeit
Pathwest Laboratory Medicine WA, Nedlands, WA, 6009, Australia.
Lim, Ee Mun;
ORCID
0000-0002-0994-0184
Zugehörigkeit
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
Linneberg, Allan;
Zugehörigkeit
Department of Medicine and Surgery, University of Parma, University Hospital of Parma, Parma, Italy.
Marina, Michela;
ORCID
0000-0003-4156-1464
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Mascalzoni, Deborah;
Zugehörigkeit
Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Matsuda, Koichi;
Zugehörigkeit
Institute for Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Medenwald, Daniel;
Zugehörigkeit
Helmholtz Zentrum München, Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany.
Meisinger, Christa;
ORCID
0000-0001-7786-7081
Zugehörigkeit
Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Meulenbelt, Ingrid;
Zugehörigkeit
Department of Data Analysis and Mathematical Modelling, Ghent University, Ghent, Belgium.
De Meyer, Tim;
Zugehörigkeit
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Meyer Zu Schwabedissen, Henriette E;
Zugehörigkeit
Institute for Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Mikolajczyk, Rafael;
Zugehörigkeit
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Moed, Matthijs;
ORCID
0000-0002-9603-0460
Zugehörigkeit
Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
Netea-Maier, Romana T;
ORCID
0000-0001-5047-4077
Zugehörigkeit
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Nolte, Ilja M;
ORCID
0000-0002-0311-8472
Zugehörigkeit
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Okada, Yukinori;
Zugehörigkeit
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Pala, Mauro;
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Pattaro, Cristian;
ORCID
0000-0002-3321-3972
Zugehörigkeit
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Pedersen, Oluf;
Zugehörigkeit
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Petersmann, Astrid;
Zugehörigkeit
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Porcu, Eleonora;
Zugehörigkeit
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.
Postmus, Iris;
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Pramstaller, Peter P;
Zugehörigkeit
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
Psaty, Bruce M;
ORCID
0000-0003-1459-413X
Zugehörigkeit
Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Ramos, Yolande F M;
Zugehörigkeit
Helmholtz Zentrum München, Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany.
Rawal, Rajesh;
Zugehörigkeit
Department of Psychology, University of Edinburgh, Edinburgh, UK.
Redmond, Paul;
ORCID
0000-0002-3746-9086
Zugehörigkeit
Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
Richards, J Brent;
Zugehörigkeit
Biobanking and Cardiovascular Epidemiology, Ghent University Hospital, Ghent, Belgium.
Rietzschel, Ernst R;
Zugehörigkeit
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Rivadeneira, Fernando;
Zugehörigkeit
Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
Roef, Greet;
Zugehörigkeit
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
Rotter, Jerome I;
Zugehörigkeit
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Sala, Cinzia F;
Zugehörigkeit
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Schlessinger, David;
Zugehörigkeit
Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Selvin, Elizabeth;
Zugehörigkeit
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Slagboom, P Eline;
ORCID
0000-0003-1095-3852
Zugehörigkeit
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
Soranzo, Nicole;
Zugehörigkeit
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Sørensen, Thorkild I A;
Zugehörigkeit
The Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Campus, Lambeth Palace Road, London, SE1 7EH, UK.
Spector, Timothy D;
Zugehörigkeit
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Starr, John M;
Zugehörigkeit
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
Stott, David J;
Zugehörigkeit
AZ Sint Jan Brugge, Brugge, Belgium.
Taes, Youri;
Zugehörigkeit
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
Taliun, Daniel;
Zugehörigkeit
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
Tanaka, Toshiko;
Zugehörigkeit
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
Thuesen, Betina;
Zugehörigkeit
Chair of Epidemiology, Ludwig-Maximilians-Universität München, at UNIKA-T Augsburg, Augsburg, Germany.
Tiller, Daniel;
Zugehörigkeit
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Toniolo, Daniela;
Zugehörigkeit
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Uitterlinden, Andre G;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Visser, W Edward;
Zugehörigkeit
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Walsh, John P;
Zugehörigkeit
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Wilson, Scott G;
Zugehörigkeit
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Wolffenbuttel, Bruce H R;
ORCID
0000-0002-3658-1375
Zugehörigkeit
Department of Biostatistics, Boston University, Boston, MA, USA.
Yang, Qiong;
Zugehörigkeit
Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University and Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
Zheng, Hou-Feng;
Zugehörigkeit
Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Cappola, Anne;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Peeters, Robin P;
Zugehörigkeit
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Naitza, Silvia;
Zugehörigkeit
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Völzke, Henry;
Zugehörigkeit
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Sanna, Serena;
ORCID
0000-0002-4671-3714
Zugehörigkeit
Department of Biometry, Epidemiology and Medical Bioinformatics, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
Köttgen, Anna;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Visser, Theo J;
Zugehörigkeit
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Medici, Marco

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.

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