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

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 hypoor hyperthyroidism. Citation: Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, 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 Editor: Mark I. McCarthy, University of Oxford, United Kingdom Received June 1, 2012; Accepted November 12, 2012; Published February 7, 2013 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. Funding: This work was supported by Intramural Research Program of the NIH (grants AG-023629, AG-15928, AG-20098, AG-027058, 263 MD 9164, 263 MD 821336,_NO1-AG-1-2109, U01 HL72515, R01 AG18728) and NIH General Clinical Research Centers Program, National Center for Research Resources (NCRR); NHLBI contracts (N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, and NHLBI grants HL080295, HL087652, HL105756, contracts N01-HC-25195 and N02-HL-6-4278); R&D contract with MedStar Research Institute; NINDS contract; National Center of Advancing Translational Technologies CTSI grant UL1TR000124; National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491; Robert Dawson Evans Endowment; Italian Ministry of Health grants ICS110.1/RF97.71 and Ricerca Finalizzata 2008; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; European Union’s Seventh Framework Programme (grant agreements FP7/2007-2011 and FP7/2007-2013, 259679, 223004 and ENGAGE project grant agreement HEALTH-F4-2007-201413, EPIGENESYS grant agreement 257082, BLUEPRINT grant agreement HEALTH-F5-2011-282510); Dutch Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007); Netherlands Organization for Scientific Research (NWO) (grants 050-060-810, 175.010.2005.011, 911-03-012, 050-060-810, MW 904-61-095, 911-03-016, 917 66344, 911-03-012, 175.010.2007.006); South Tyrolean Sparkasse Foundation; Radboud University Nijmegen Medical Centre; University of Maryland General Clinical Research Center grant M01 RR 16500; Johns Hopkins University General Clinical Research Center, grant M01 RR 000052; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC); Netherlands Research Institute for Diseases in the Elderly (grant 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 grants 01 AK 803 A-H, 01 IG 07015 G; Wellcome Trust (grants WT089062, WT098051, 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 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 (grants 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’’ (grant 050-060-810); 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; 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 and programme grants from 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 grant 2001 D 032; National Computing Facilities Foundation (NCF), Netherlands, for the use of supercomputer facilities; Endocrine Research Fund; http://www.chs-nhlbi.org/pi.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Genetic Regulation of Thyroid Function PLOS Genetics | www.plosgenetics.org 2 February 2013 | Volume 9 | Issue 2 | e1003266 Competing Interests: The authors have declared that no competing interests exist. * E-mail: serena.sanna@irgb.cnr.it (S Sanna); r.peeters@erasmusmc.nl (RP Peeters); silvia.naitza@irgb.cnr.it (S Naitza) ¤a Current address: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy ¤b Current address: Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy . These authors contributed equally to this work. " These authors also contributed equally to this work.