@article{Porcu2013, abstract = {Published ; Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; 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. ; Intramural Research Program of the NIH ; NCRR ; NHLBI ; MedStar Research Institute ; NINDS ; National Center of Advancing Translational Technologies CTSI ; National Institute of Diabetes and Digestive and Kidney Diseases ; Robert Dawson Evans Endowment ; Italian Ministry of Health ; University and Research of the Autonomous Province of Bolzano ; European Union's Seventh Framework Programme ; ENGAGE project ; EPIGENESYS ; BLUEPRINT ; Dutch Innovation-Oriented Research Program on Genomics ; Netherlands Organization for Scientific Research (NWO) ; South Tyrolean Sparkasse Foundation ; Radboud University Nijmegen Medical Centre ; University of Maryland General Clinical Research Center ; Johns Hopkins University General Clinical Research Center ; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC) ; Netherlands Research Institute for Diseases in the Elderly ; 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 ; Municipality of Rotterdam ; German Bundesministerium fuer Forschung und Technology ; Wellcome Trust ; 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 Santé Québec, Ministère du Développement Économique, de l'Innovation et de l'Exportation ; Lady Davis Institute of the Jewish General Hospital (JBR) ; Australian National Health and Medical Research Council ; 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 ; Academy of Finland ; Finnish Diabetes Research Society ; Folkhälsan Research Foundation ; Novo Nordisk Foundation ; Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation ; University of Helsinki ; European Science Foundation (EUROSTRESS) ; Finnish Ministry of Education ; Ahokas Foundation ; Emil Aaltonen Foundation ; Juho Vainio Foundation ; BBSRC ; EPSRC ; ESRC ; MRC ; AXA Research Fund ; 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 ; Dutch Diabetes Research Foundation ; Bristol-Myers Squibb ; Netherlands Heart Foundation ; National Computing Facilities Foundation (NCF), Netherlands ; Endocrine Research Fund}, author = {Porcu, Eleonora and Brown, Stephen and Medici, Marco and Pistis, Giorgio and Cb, Volpato and Klauw, Melanie and Sg, Wilson and Volpato, Claudia B. and Wilson, Scott G. and Bos, Steffan D. and Ar, Cappola and Cappola, Anne R. and Sd, Bos and Deelen, Joris and den Heijer, Martin and Rm, Freathy and Lahti, Jari and Rivadeneira Ramirez, Fernando and Freathy, Rachel M. and Liu, Chunyu and Heijer, Martin den and Lm, Lopez and Im, Nolte and Lopez, Lorna M. and Nolte, Ilja M. and O´connell, Jeffrey R. and Kiemeney, Bart and Jr, O'Connell and Tanaka, Toshiko and Trompet, Stella and Arnold, Alice and Bandinelli, Stefania and Beekman, Marian and Böhringer, Stefan and Sj, Brown and Bohringer, Stefan and Bm, Buckley and Buckley, Brendan M. and Camaschella, Clara and Aj, de Craen and de Craen, Anton J. M. and Mc, de Visser and Davies, Gail and de Visser, Marieke C. H. and Spector, Timothy and Visser, Marieke C. and Ford, Ian and Forsen, Tom and Tm, Frayling and Frayling, Timothy M. and Goegele, Martin and Fugazzola, Laura and Gögele, Martin and At, Hattersley and Hattersley, Andrew T. and Hermus, Ad R. and Ar, Hermus and Hofman, Albert and Jj, Houwing Duistermaat and Houwing-Duistermaat, Jeanine Jj and Jensen, Richard A. and Ra, Jensen and Kajantie, Eero and Em, Lim and Kloppenburg, Margreet and Uitterlinden, André G. and Lim, Ee M. and Masciullo, Corrado and Bd, Mitchell and Mariotti, Stefano and Rt, Netea Maier and Minelli, Cosetta and Mitchell, Braxton D. and Visser, Ton and Nagaraja, Ramaiah and Mg, Piras and Netea-Maier, Romana T. and Bm, Psaty and Palotie, Aarno and Persani, Luca and Brent Richards, J. and Piras, Maria Grazia and Jb, Richards and Psaty, Bruce M. and Räikkönen, Katri and Böhringer, Stefan and Richards, Jb Brent and Mm, Sabra and Bm, Shields and Sala, Cinzia and Räikkönen, Katri and Sabra, Mona Mm and Jm, Starr and Sattar, Naveed and Dj, Stott and Shields, Beverley M. and Soranzo, Nicole and Fc, Sweep and Starr, John M. and Mm, van der Klauw and Stott, David J. and Sweep, Fred C. G. J. and Edward Visser, W. and Usala, Gianluca and Vermeulen, Sita H. and van der Klauw, Melanie Mm and van Heemst, Diana and Visser, We and van Mullem, Alies and Sh, Vermeulen and Visser, W. Edward and Jp, Walsh and Rg, Westendorp and H. Vermeulen, Sita and Walsh, John P. and Westendorp, Rudi G. J. and Ij, Deary and Widen, Elisabeth and Zhai, Guangju and Jg, Eriksson and Cucca, Francesco and Craen, A. J. and Deary, Ian J. and Eriksson, Johan G. and Cs, Fox and Ferrucci, Luigi and Wouter Jukema, J. and Jw, Jukema and Kiemeney, La and Jukema, Jan Wouter and Pp, Pramstaller and Kiemeney, Lambertus A. and Pramstaller, Peter Paul and Ar, Shuldiner and Schlessinger, David and Shuldiner, Alan R. and Ep, Slagboom and Slagboom, Eline P. and Slagboom, P. Eline and Ag, Uitterlinden and Visser, Theo J. and Vaidya, Bijay and Visser, Tj and Fox, Craig and Wolffenbuttel, Bruce H. R. and Bh, Wolffenbuttel and Meulenbelt, Ingrid and Rotter, Jerome I. and Ji, Rotter and Td, Spector and Heemst, Diana and Hicks, Andrew Aa and Aa, Hicks and Toniolo, Daniela and Visser, Willy and Sanna, Serena and Peeters, Robin P. and Rp, Peeters and Mullem, Alies and Naitza, Silvia}, doi = {10.1371/journal.pgen.1003266}, month = {feb}, title = {A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function}, url = {http://dx.doi.org/10.1371/journal.pgen.1003266}, year = {2013} }