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

dc.contributor.authorPorcu, Eleonora
dc.contributor.authorMedici, Marco
dc.contributor.authorPistis, Giorgio
dc.contributor.authorVolpato, Claudia B.
dc.contributor.authorWilson, Scott G.
dc.contributor.authorCappola, Anne R.
dc.contributor.authorBos, Steffan D.
dc.contributor.authorDeelen, Joris
dc.contributor.authorden Heijer, Martin
dc.contributor.authorFreathy, Rachel M.
dc.contributor.authorLahti, Jari
dc.contributor.authorLiu, Chunyu
dc.contributor.authorLopez, Lorna M.
dc.contributor.authorNolte, Ilja M.
dc.contributor.authorO'Connell, Jeffrey R.
dc.contributor.authorTanaka, Toshiko
dc.contributor.authorTrompet, Stella
dc.contributor.authorArnold, Alice
dc.contributor.authorBandinelli, Stefania
dc.contributor.authorBeekman, Marian
dc.contributor.authorBohringer, Stefan
dc.contributor.authorBrown, Suzanne J.
dc.contributor.authorBuckley, Brendan M.
dc.contributor.authorCamaschella, Clara
dc.contributor.authorde Craen, Anton J. M.
dc.contributor.authorDavies, Gail
dc.contributor.authorde Visser, Marieke C. H.
dc.contributor.authorFord, Ian
dc.contributor.authorForsen, Tom
dc.contributor.authorFrayling, Timothy M.
dc.contributor.authorFugazzola, Laura
dc.contributor.authorGoegele, Martin
dc.contributor.authorHattersley, Andrew T.
dc.contributor.authorHermus, Ad R.
dc.contributor.authorHofman, Albert
dc.contributor.authorHouwing-Duistermaat, Jeanine J.
dc.contributor.authorJensen, Richard A.
dc.contributor.authorKajantie, Eero
dc.contributor.authorKloppenburg, Margreet
dc.contributor.authorLim, Ee M.
dc.contributor.authorMasciullo, Corrado
dc.contributor.authorMariotti, Stefano
dc.contributor.authorMinelli, Cosetta
dc.contributor.authorMitchell, Braxton D.
dc.contributor.authorNagaraja, Ramaiah
dc.contributor.authorNetea-Maier, Romana T.
dc.contributor.authorPalotie, Aarno
dc.contributor.authorPersani, Luca
dc.contributor.authorPiras, Maria G.
dc.contributor.authorPsaty, Bruce M.
dc.contributor.authorRäikkönen, Katri
dc.contributor.authorRichards, J. Brent
dc.contributor.authorRivadeneira, Fernando
dc.contributor.authorSala, Cinzia
dc.contributor.authorSabra, Mona M.
dc.contributor.authorSattar, Naveed
dc.contributor.authorShields, Beverley M.
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorStarr, John M.
dc.contributor.authorStott, David J.
dc.contributor.authorSweep, Fred C. G. J.
dc.contributor.authorUsala, Gianluca
dc.contributor.authorvan der Klauw, Melanie M.
dc.contributor.authorvan Heemst, Diana
dc.contributor.authorvan Mullem, Alies
dc.contributor.authorVermeulen, Sita H.
dc.contributor.authorVisser, W. Edward
dc.contributor.authorWalsh, John P.
dc.contributor.authorWestendorp, Rudi G. J.
dc.contributor.authorWiden, Elisabeth
dc.contributor.authorZhai, Guangju
dc.contributor.authorCucca, Francesco
dc.contributor.authorDeary, Ian J.
dc.contributor.authorEriksson, Johan
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorFox, Caroline S.
dc.contributor.authorJukema, J. Wouter
dc.contributor.authorKiemeney, Lambertus A.
dc.contributor.authorPramstaller, Peter P.
dc.contributor.authorSchlessinger, David
dc.contributor.authorShuldiner, Alan R.
dc.contributor.authorSlagboom, P. Eline
dc.contributor.authorUitterlinden, Andre G.
dc.contributor.authorVaidya, Bijay
dc.contributor.authorVisser, Theo J.
dc.contributor.authorWolffenbuttel, Bruce H. R.
dc.contributor.authorMeulenbelt, Ingrid
dc.contributor.authorRotter, Jerome I.
dc.contributor.authorSpector, Tim D.
dc.contributor.authorHicks, Andrew A.
dc.contributor.authorToniolo, Daniela
dc.contributor.authorSanna, Serena
dc.contributor.authorPeeters, Robin P.
dc.contributor.authorNaitza, Silvia
dc.description.abstractThyroid 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.sponsorshipNIH (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 Funden
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.identifier.citationPorcu 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.1003266en
dc.identifier.journaltitlePLOS GENETICSen
dc.publisherPublic Library of Scienceen
dc.rightsThis 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.subjectGenome wide Associationen
dc.subjectFactor binding protein 5en
dc.subjectHormone pathway genesen
dc.subjectSerum TSHen
dc.subjectCommon variationen
dc.subjectCleft palateen
dc.titleA meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid functionen
dc.typeArticle (peer-reviewed)en
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