Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation
Alexander Teumer(Universitätsmedizin Greifswald), Layal Chaker(Erasmus MC), Stefan Groeneweg(Erasmus MC), Yong Li(University of Freiburg), Celia Di Munno(University of Sannio), Caterina Barbieri, Ulla T. Schultheiß(University of Freiburg), Michela Traglia, Tarunveer S. Ahluwalia(University of Copenhagen), Masato Akiyama(RIKEN Center for Integrative Medical Sciences), Emil V. R. Appel(University of Copenhagen), Dan E. Arking(Johns Hopkins University), Alice M. Arnold(University of Washington), Arne Astrup(University of Copenhagen), Marian Beekman(Leiden University Medical Center), John Beilby(The University of Western Australia), Sofie Bekaert(Ghent University Hospital), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Suzanne J. Brown(Sir Charles Gairdner Hospital), Marc De Buyzere(Ghent University Hospital), Purdey J. Campbell(Sir Charles Gairdner Hospital), Graziano Ceresini(University of Parma), Charlotte Cerqueira(Frederiksberg Hospital), Francesco Cucca(University of Sassari), Ian J. Deary(University of Edinburgh), Joris Deelen(Leiden University Medical Center), Kai‐Uwe Eckardt(Friedrich-Alexander-Universität Erlangen-Nürnberg), Arif B. Ekici(Friedrich-Alexander-Universität Erlangen-Nürnberg), Johan G. Eriksson(University of Helsinki), Luigi Ferrrucci(National Institute on Aging), Tom Fiers(Ghent University Hospital), Edoardo Fiorillo(Institute of Genetic and Biomedical Research), Ian Ford(University of Glasgow), Caroline S. Fox(Brigham and Women's Hospital), Christian Fuchsberger(Eurac Research), Tessel E. Galesloot(Radboud University Nijmegen), Christian Gieger(Helmholtz Zentrum München), Martin Gögele(Eurac Research), Alessandro De Grandi(Eurac Research), Niels Grarup(University of Copenhagen), Karin Halina Greiser(German Cancer Research Center), Kadri Haljas(University of Helsinki), Torben Hansen(University of Copenhagen), Sarah E. Harris(Institute of Genetics and Cancer), Diana van Heemst(Leiden University Medical Center), Martin den Heijer(Vrije Universiteit Amsterdam), Andrew A. Hicks(Eurac Research), Wouter den Hollander(Leiden University Medical Center), Georg Homuth(Universitätsmedizin Greifswald), Jennie Hui(The University of Western Australia), M. Arfan Ikram(Erasmus MC), Till Ittermann(Universitätsmedizin Greifswald), Richard A. Jensen(University of Washington), Jiaojiao Jing(University of Freiburg), J. Wouter Jukema(Leiden University Medical Center), Eero Kajantie(University of Helsinki), Yoichiro Kamatani(Kyoto University), Elisa Kasbohm(Friedrich-Loeffler-Institut), Jean‐Marc Kaufman(Ghent University Hospital), Lambertus A. Kiemeney(Radboud University Nijmegen), M. Kloppenburg(Leiden University Medical Center), Florian Kronenberg(Innsbruck Medical University), Michiaki Kubo(RIKEN Center for Integrative Medical Sciences), Jari Lahti(University of Helsinki), Bruno Lapauw(Ghent University Hospital), Shuo Li(Boston University), David C. Liewald(University of Edinburgh), Lifelines Cohort Study, Behrooz Z. Alizadeh, H. Marike Boezen, Lude Franke, Pim van der Harst, Gerjan Navis, Marianne G. Rots, Harold Snieder, Morris A. Swertz, Cisca Wijmenga(Sir Charles Gairdner Hospital), Ee Mun Lim(Frederiksberg Hospital), Allan Linneberg(University of Parma), Michela Marina(University of Parma), Deborah Mascalzoni(Eurac Research), Koichi Matsuda(Martin Luther University Halle-Wittenberg), Daniel Medenwald(University of Augsburg), Christa Meisinger(University of Augsburg), Ingrid Meulenbelt(Leiden University Medical Center), Tim De Meyer(University of Basel), Henriette E. Meyer zu Schwabedissen(University of Basel), Rafael Mikolajczyk(Leiden University Medical Center), Matthijs Moed(Radboud University Nijmegen), Romana T. Netea‐Maier(University Medical Center Groningen), Ilja M. Nolte(University Medical Center Groningen), Yukinori Okada(Institute of Genetic and Biomedical Research), Mauro Pala(Eurac Research), Cristian Pattaro(University of Copenhagen), Oluf Pedersen(University of Copenhagen), Astrid Petersmann(SIB Swiss Institute of Bioinformatics), Eleonora Porcu(SIB Swiss Institute of Bioinformatics), Iris Postmus(Eurac Research), Peter P. Pramstaller(Eurac Research), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), Y.F. Ramos(Leiden University Medical Center), Rajesh Rawal(Helmholtz Zentrum München), Paul Redmond(King's College London), J. Brent Richards(King's College London), Ernst Rietzschel(Ghent University Hospital), Fernando Rivadeneira(Ghent University Hospital), Greet Roef(The Lundquist Institute), Jerome I. Rotter(The Lundquist Institute), Cinzia Sala(National Institutes of Health), David Schlessinger(National Institutes of Health), Elizabeth Selvin(Johns Hopkins University), P. Eline Slagboom(Leiden University Medical Center), Nicole Soranzo(University of Copenhagen), Thorkild I. A. Sørensen(University of Copenhagen), Timothy D. Spector(King's College London), John M. Starr(Alzheimer Scotland), David J. Stott(AZ Sint-Jan), Youri Taes(Eurac Research), Daniel Taliun(Eurac Research), Toshiko Tanaka(Frederiksberg Hospital), Betina H. Thuesen(University of Augsburg), Daniel Tiller(University of Augsburg), Daniela Toniolo(Erasmus MC), André G. Uitterlinden(Erasmus MC), W. Edward Visser(The University of Western Australia), John P. Walsh(The University of Western Australia), Scott G. Wilson(University Medical Center Groningen), Bruce H. R. Wolffenbuttel(Boston University), Qiong Yang(Boston University), Hou‐Feng Zheng(Westlake University), Anne Rentoumis Cappola(Erasmus MC), Robin P. Peeters(Erasmus MC), Silvia Naitza(Universitätsmedizin Greifswald), Henry Völzke(University Medical Center Groningen), Serena Sanna(University Medical Center Groningen), Anna Köttgen(Johns Hopkins University), Theo J. Visser(Erasmus MC), Marco Medici(Erasmus MC)
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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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