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Nat Commun. 2018 Oct 26;9(1):4455. doi: 10.1038/s41467-018-06356-1.

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

Teumer A1,2, Chaker L3,4,5, Groeneweg S3,5, Li Y6, Di Munno C3,7, Barbieri C8, Schultheiss UT6, Traglia M8, Ahluwalia TS9,10, Akiyama M11, Appel EVR10, Arking DE12, Arnold A13, Astrup A14, Beekman M15, Beilby JP16,17, Bekaert S18, Boerwinkle E19, Brown SJ20, De Buyzere M21, Campbell PJ20, Ceresini G22, Cerqueira C23, Cucca F24,25, Deary IJ26,27, Deelen J15,28, Eckardt KU29,30, Ekici AB31, Eriksson JG32,33,34, Ferrrucci L35, Fiers T36, Fiorillo E24, Ford I37, Fox CS38,39, Fuchsberger C40, Galesloot TE41, Gieger C42,43, Gögele M40, De Grandi A40, Grarup N10, Greiser KH44, Haljas K45, Hansen T10, Harris SE26,46, van Heemst D47, den Heijer M48, Hicks AA40, den Hollander W49, Homuth G50, Hui J16,51, Ikram MA4, Ittermann T52,53, Jensen RA54, Jing J6,55, Jukema JW56,57, Kajantie E34,58,59, Kamatani Y11,60, Kasbohm E52,61, Kaufman JM62, Kiemeney LA41, Kloppenburg M63,64, Kronenberg F65, Kubo M66, Lahti J45, Lapauw B62, Li S67, Liewald DCM26,27; Lifelines Cohort Study, Lim EM16,20, Linneberg A23,68, Marina M22, Mascalzoni D40, Matsuda K69, Medenwald D70, Meisinger C42,71, Meulenbelt I49, De Meyer T72, Meyer Zu Schwabedissen HE73, Mikolajczyk R70, Moed M15, Netea-Maier RT74, Nolte IM75, Okada Y11,76,77, Pala M24, Pattaro C40, Pedersen O10, Petersmann A78, Porcu E24,79, Postmus I80, Pramstaller PP40, Psaty BM81,82, Ramos YFM49, Rawal R42, Redmond P27, Richards JB83,84, Rietzschel ER85,86, Rivadeneira F4,5, Roef G62, Rotter JI87, Sala CF8, Schlessinger D88, Selvin E89, Slagboom PE15, Soranzo N90, Sørensen TIA10,91, Spector TD84, Starr JM26,92, Stott DJ93, Taes Y94, Taliun D40, Tanaka T35, Thuesen B23, Tiller D71, Toniolo D8, Uitterlinden AG4,5, Visser WE3,5, Walsh JP20,51, Wilson SG20,51,84, Wolffenbuttel BHR95, Yang Q67, Zheng HF96,97, Cappola A98, Peeters RP3,5, Naitza S24, Völzke H52,53, Sanna S24,99, Köttgen A6,100, Visser TJ3,5, Medici M3,4,5.

Author information

1
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. ateumer@uni-greifswald.de.
2
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany. ateumer@uni-greifswald.de.
3
Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
4
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
5
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
6
Department of Biometry, Epidemiology and Medical Bioinformatics, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
7
Department of Science and Technologies, University of Sannio, Benevento, Italy.
8
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
9
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
10
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
11
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
12
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
13
Department of Biostatistics, University of Washington, Seattle, WA, USA.
14
Department of Nutrition, Exercise, and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
15
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
16
Pathwest Laboratory Medicine WA, Nedlands, WA, 6009, Australia.
17
School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia.
18
Bimetra, Clinical Research Center Ghent, Ghent University Hospital, Ghent, Belgium.
19
Human Genetics Center, University of Texas Health Science Center, 1200 Pressler Street, Houston, TX, 77030, USA.
20
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
21
Department of Cardiology, Ghent University Hospital, Ghent, Belgium.
22
Department of Medicine and Surgery, University of Parma, University Hospital of Parma, Parma, Italy.
23
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
24
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
25
Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
26
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
27
Department of Psychology, University of Edinburgh, Edinburgh, UK.
28
Max Planck Institute for Biology of Ageing, Cologne, Germany.
29
Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany.
30
Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.
31
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
32
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
33
Folkhälsan Research Center, Helsinki, Finland.
34
National Institute for Health and Welfare, Helsinki, Finland.
35
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
36
Department of Clinical Chemistry, Ghent University Hospital, Ghent, Belgium.
37
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
38
National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA, USA.
39
Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
40
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy.
41
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
42
Helmholtz Zentrum München, Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany.
43
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
44
German Research Centre Division of Cancer Epidemiology, Heidelberg, Germany.
45
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
46
Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK.
47
Leiden University Medical Center, Geriatrics and Gerontology, Leiden, The Netherlands.
48
Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
49
Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
50
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
51
Medical School, University of Western Australia, Crawley, WA, 6009, Australia.
52
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
53
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
54
Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
55
Faculty of Biology, University of Freiburg, Freiburg, Germany.
56
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
57
Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
58
Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
59
PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
60
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
61
Institute of Epidemiology, Friedrich-Loeffler-Institut (FLI), Federal Research Institute for Animal Health, Greifswald, Germany.
62
Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
63
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
64
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
65
Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
66
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
67
Department of Biostatistics, Boston University, Boston, MA, USA.
68
Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
69
Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
70
Institute for Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
71
Chair of Epidemiology, Ludwig-Maximilians-Universität München, at UNIKA-T Augsburg, Augsburg, Germany.
72
Department of Data Analysis and Mathematical Modelling, Ghent University, Ghent, Belgium.
73
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
74
Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
75
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
76
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
77
Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
78
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
79
Center for Integrative Genomics, University of Lausanne, and Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland.
80
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.
81
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
82
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
83
Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
84
The Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Campus, Lambeth Palace Road, London, SE1 7EH, UK.
85
Biobanking and Cardiovascular Epidemiology, Ghent University Hospital, Ghent, Belgium.
86
Department of Internal Medicine (Cardiology), Ghent University, Ghent, Belgium.
87
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
88
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
89
Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
90
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
91
Department of Public Health (Section on Epidemiology), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
92
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
93
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
94
AZ Sint Jan Brugge, Brugge, Belgium.
95
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
96
Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University and Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
97
Institute of Aging Research and the Affiliated Hospital, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
98
Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
99
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
100
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 625 N Wolfe Street, Baltimore, MD, 21205, USA.

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.

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