TY - JOUR
T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation
AU - Lifelines Cohort Study
AU - Teumer, Alexander
AU - Chaker, Layal
AU - Groeneweg, Stefan
AU - Li, Yong
AU - Di Munno, Celia
AU - Barbieri, Caterina
AU - Schultheiss, Ulla T.
AU - Traglia, Michela
AU - Ahluwalia, Tarunveer S.
AU - Akiyama, Masato
AU - Appel, Emil Vincent R.
AU - Arking, Dan E.
AU - Arnold, Alice
AU - Astrup, Arne
AU - Beekman, Marian
AU - Beilby, John P.
AU - Bekaert, Sofie
AU - Boerwinkle, Eric
AU - Brown, Suzanne J.
AU - De Buyzere, Marc
AU - Campbell, Purdey J.
AU - Ceresini, Graziano
AU - Cerqueira, Charlotte
AU - Cucca, Francesco
AU - Deary, Ian J.
AU - Deelen, Joris
AU - Eckardt, Kai Uwe
AU - Ekici, Arif B.
AU - Eriksson, Johan G.
AU - Ferrrucci, Luigi
AU - Fiers, Tom
AU - Fiorillo, Edoardo
AU - Ford, Ian
AU - Fox, Caroline S.
AU - Fuchsberger, Christian
AU - Galesloot, Tessel E.
AU - Gieger, Christian
AU - Gögele, Martin
AU - De Grandi, Alessandro
AU - Grarup, Niels
AU - Greiser, Karin Halina
AU - Haljas, Kadri
AU - Hansen, Torben
AU - Harris, Sarah E.
AU - van Heemst, Diana
AU - den Heijer, Martin
AU - Hicks, Andrew A.
AU - den Hollander, Wouter
AU - Homuth, Georg
AU - Hui, Jennie
N1 - Funding Information:
10Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 11Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 12McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 13Department of Biostatistics, University of Washington, Seattle, WA, USA. 14Department of Nutrition, Exercise, and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. 15Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands. 16Pathwest Laboratory Medicine WA, Nedlands, WA 6009, Australia. 17School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia. 18Bimetra, Clinical Research Center Ghent, Ghent University Hospital, Ghent, Belgium. 19Human Genetics Center, University of Texas Health Science Center, 1200 Pressler Street, Houston, TX 77030, USA. 20Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia. 21Department of Cardiology, Ghent University Hospital, Ghent, Belgium. 22Department of Medicine and Surgery, University of Parma, University Hospital of Parma, Parma, Italy. 23Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark. 24Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy. 25Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy. 26Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. 27Department of Psychology, University of Edinburgh, Edinburgh, UK. 28Max Planck Institute for Biology of Ageing, Cologne, Germany. 29Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany.
Funding Information:
Competing interests: B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The remaining authors declare no competing interests.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-06356-1
DO - 10.1038/s41467-018-06356-1
M3 - Article
C2 - 30367059
AN - SCOPUS:85055612686
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4455
ER -
