A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

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dc.contributor.author Porcu, Eleonora
dc.contributor.author Medici, Marco
dc.contributor.author Pistis, Giorgio
dc.contributor.author Volpato, Claudia B.
dc.contributor.author Wilson, Scott G.
dc.contributor.author Cappola, Anne R.
dc.contributor.author Bos, Steffan D.
dc.contributor.author Deelen, Joris
dc.contributor.author den Heijer, Martin
dc.contributor.author Freathy, Rachel M.
dc.contributor.author Lahti, Jari
dc.contributor.author Liu, Chunyu
dc.contributor.author Lopez, Lorna M.
dc.contributor.author Nolte, Ilja M.
dc.contributor.author O'Connell, Jeffrey R.
dc.contributor.author Tanaka, Toshiko
dc.contributor.author Trompet, Stella
dc.contributor.author Arnold, Alice
dc.contributor.author Bandinelli, Stefania
dc.contributor.author Beekman, Marian
dc.contributor.author Bohringer, Stefan
dc.contributor.author Brown, Suzanne J.
dc.contributor.author Buckley, Brendan M.
dc.contributor.author Camaschella, Clara
dc.contributor.author de Craen, Anton J. M.
dc.contributor.author Davies, Gail
dc.contributor.author de Visser, Marieke C. H.
dc.contributor.author Ford, Ian
dc.contributor.author Forsen, Tom
dc.contributor.author Frayling, Timothy M.
dc.contributor.author Fugazzola, Laura
dc.contributor.author Goegele, Martin
dc.contributor.author Hattersley, Andrew T.
dc.contributor.author Hermus, Ad R.
dc.contributor.author Hofman, Albert
dc.contributor.author Houwing-Duistermaat, Jeanine J.
dc.contributor.author Jensen, Richard A.
dc.contributor.author Kajantie, Eero
dc.contributor.author Kloppenburg, Margreet
dc.contributor.author Lim, Ee M.
dc.contributor.author Masciullo, Corrado
dc.contributor.author Mariotti, Stefano
dc.contributor.author Minelli, Cosetta
dc.contributor.author Mitchell, Braxton D.
dc.contributor.author Nagaraja, Ramaiah
dc.contributor.author Netea-Maier, Romana T.
dc.contributor.author Palotie, Aarno
dc.contributor.author Persani, Luca
dc.contributor.author Piras, Maria G.
dc.contributor.author Psaty, Bruce M.
dc.contributor.author Räikkönen, Katri
dc.contributor.author Richards, J. Brent
dc.contributor.author Rivadeneira, Fernando
dc.contributor.author Sala, Cinzia
dc.contributor.author Sabra, Mona M.
dc.contributor.author Sattar, Naveed
dc.contributor.author Shields, Beverley M.
dc.contributor.author Soranzo, Nicole
dc.contributor.author Starr, John M.
dc.contributor.author Stott, David J.
dc.contributor.author Sweep, Fred C. G. J.
dc.contributor.author Usala, Gianluca
dc.contributor.author van der Klauw, Melanie M.
dc.contributor.author van Heemst, Diana
dc.contributor.author van Mullem, Alies
dc.contributor.author Vermeulen, Sita H.
dc.contributor.author Visser, W. Edward
dc.contributor.author Walsh, John P.
dc.contributor.author Westendorp, Rudi G. J.
dc.contributor.author Widen, Elisabeth
dc.contributor.author Zhai, Guangju
dc.contributor.author Cucca, Francesco
dc.contributor.author Deary, Ian J.
dc.contributor.author Eriksson, Johan G.
dc.contributor.author Ferrucci, Luigi
dc.contributor.author Fox, Caroline S.
dc.contributor.author Jukema, J. Wouter
dc.contributor.author Kiemeney, Lambertus A.
dc.contributor.author Pramstaller, Peter P.
dc.contributor.author Schlessinger, David
dc.contributor.author Shuldiner, Alan R.
dc.contributor.author Slagboom, P. Eline
dc.contributor.author Uitterlinden, Andre G.
dc.contributor.author Vaidya, Bijay
dc.contributor.author Visser, Theo J.
dc.contributor.author Wolffenbuttel, Bruce H. R.
dc.contributor.author Meulenbelt, Ingrid
dc.contributor.author Rotter, Jerome I.
dc.contributor.author Spector, Tim D.
dc.contributor.author Hicks, Andrew A.
dc.contributor.author Toniolo, Daniela
dc.contributor.author Sanna, Serena
dc.contributor.author Peeters, Robin P.
dc.contributor.author Naitza, Silvia
dc.date.accessioned 2016-02-17T11:46:20Z
dc.date.available 2016-02-17T11:46:20Z
dc.date.issued 2013
dc.identifier.citation Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, et al. (2013) A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function. PLoS Genet 9(2): e1003266. doi:10.1371/journal.pgen.1003266 en
dc.identifier.volume 9 en
dc.identifier.issued 2 en
dc.identifier.issn 1553-7404
dc.identifier.uri http://hdl.handle.net/10468/2394
dc.identifier.doi 10.1371/journal.pgen.1003266
dc.description.abstract Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. en
dc.description.sponsorship NIH (AG-023629, AG-15928, AG-20098, AG-027058, 263 MD 9164, 263 MD 821336,, _NO1-AG-1-2109, U01 HL72515, R01 AG18728); NIH General Clinical Research Centers Program, National Center for Research Resources (NCRR); NHLBI (N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756, N01-HC-25195, N02-HL-6-4278); MedStar Research Institute; NINDS; National Center of Advancing Translational Technologies CTSI (UL1TR000124); National Institute of Diabetes and Digestive and Kidney Diseases (DK063491); Robert Dawson Evans Endowment; Italian Ministry of Health (ICS110.1/RF97.71); Ricerca Finalizzata; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; European Union (259679, 223004, HEALTH-F4-2007-201413, 257082, HEALTH-F5-2011-282510); Dutch Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007); Netherlands Organization for Scientific Research (NWO) (050-060-810, 75.010.2005.011, 911-03-012, MW 904-61-095, 911-03-016, 917 66344, 175.010.2007.006); South Tyrolean Sparkasse Foundation; Radboud University Nijmegen Medical Centre; University of Maryland General Clinical Research Center (M01 RR 16500); Johns Hopkins University General Clinical Research Center (M01 RR 000052); Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC); Netherlands Research Institute for Diseases in the Elderly (014-93-015, RIDE2); Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Dutch Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); Wellcome Trust (WT089062, WT091310, 085541/Z/08/Z); English Department of Health, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; Canadian Institutes of Health Research; Canadian Foundation for Innovation; Fonds de la Recherche en Sante Quebec; Ministere du Developpement Economique, de l'Innovation et de l'Exportation;; Lady Davis Institute of the Jewish General Hospital (JBR); Australian National Health and Medical Research Council (1010494, 1031422); Sir Charles Gairdner Hospital Research Fund; Italian "Compagnia di San Paolo''; Italian "Fondazione Cariplo''; Leiden University Medical Centre; Dutch Arthritis Association; Pfizer, Groton, CT, USA; Dutch Centre of Medical System Biology; Netherlands Genomics Initiative (NGI); Netherlands Consortium of Healthy Aging (050-060-810); Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Finnish Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative; AXA Research Fund; Research Into Ageing; Help the Aged/Research Into Ageing (Disconnected Mind); Economic Structure Enhancing Fund (FES) of the Dutch government; Dutch Ministry of Economic Affairs; Dutch Ministry of Education, Culture and Science; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University of Groningen; Dutch Kidney Foundation and Dutch Diabetes Research Foundation; Bristol-Myers Squibb; Netherlands Heart Foundation (2001 D 032); National Computing Facilities Foundation (NCF), Netherlands; Endocrine Research Fund en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Public Library of Science en
dc.rights This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. en
dc.rights.uri https://creativecommons.org/publicdomain/zero/1.0/ en
dc.subject Genome wide Association en
dc.subject Factor binding protein 5 en
dc.subject Hormone pathway genes en
dc.subject Serum TSH en
dc.subject Common variation en
dc.subject Cleft palate en
dc.subject Expression en
dc.subject Growth en
dc.subject Hypothyroidism en
dc.subject Thyrotropin en
dc.title A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Brendan M. Buckley, Pharmacology and Therapeutics, University College Cork, Cork, Ireland. +353-21-490-3000 Email: b.buckley@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.internal.wokid WOS:000315638300025
dc.description.status Peer reviewed en
dc.identifier.journaltitle PLOS GENETICS en
dc.internal.IRISemailaddress b.buckley@ucc.ie en
dc.identifier.articleid e1003266


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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Except where otherwise noted, this item's license is described as This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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