FHS (Framingham Heart Study) is funded by National Institutes of Health (NIH) contract N01-HC-25195 and HHSN268201500001I and administered by Boston University. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), NIH, and an NIH Director's Challenge Award (Dr Levy, Principal Investigator). The analytic component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study used the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/). Dr Mendelson is partly supported by the Tommy Kaplan Fund, Boston Children's Hospital. Dr Liang is partially supported by NIH grant P30 DK46200. Dr Ingelsson is supported by Knut and Alice Wallenberg (KAW) Foundation, Swedish Research Council (VR; grant no. 2012-1397), Swedish Heart-Lung Foundation (20120197) NIH grants 1R01DK106236-01A1 and 1R01HL135313-01. Genome-wide DNA methylation profiling in PIVUS was funded by the Uppsala University Hospital (ALF-medel) and was performed by the SNP&SEQ Technology Platform in Uppsala. The facility is part of the National Genomics Infrastructure Sweden and Science for Life Laboratory. The SNP&SEQ Platform is also supported by the VR and the KAW Foundation. Phenotype collection in the LBC1921 (Lothian Birth Cohorts of 1921) study was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the LBC1936 (Lothian Birth Cohorts of 1936) study was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by the Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE; Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. Drs Marioni, Starr, and Deary are members of the University of Edinburgh CCACE. CCACE is supported by funding from the BBSRC, the Medical Research Council and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). Research reported in this publication was supported by National Health and Medical Research Council (NHMRC) project grant 1010374 and an NHMRC Fellowship to Dr McRae (1083656). The GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study was supported by NIH National Heart, Lung and Blood Institute grant R01 HL104135-01. The MuTHER study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007–2013). The study as part of TwinsUK also receives support from the Medical Research Council, European Union, National Institute for Health Research-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. Dr Spector is a holder of an European Research Council Advanced Principal Investigator award.
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
Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (41071, 77299, 102318, 110413, 117787, 121584, 123885, 124243, 124282, 126925, 129378, 134309, 286284); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la 359 Recherche; Agency for Health Care Policy Research (HS06516); ALF/LUA research grant in Gothenburg; ALFEDIAM; ALK-Abello´ A/S; Althingi; American Heart Association (13POST16500011); Amgen; Andrea and Charles Bronfman Philanthropies; Ardix Medical; Arthritis Research UK; Association Diabe`te Risque Vasculaire; Australian National Health and Medical Research Council (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496739, 552485, 552498); Avera Institute; Bayer Diagnostics; Becton Dickinson; BHF (RG/14/5/30893); Boston Obesity Nutrition Research Center (DK46200), Bristol-Myers Squibb; British Heart Foundation (RG/10/12/ 28456, RG2008/08, RG2008/014, SP/04/002); Medical Research Council of Canada; Canadian Institutes for Health Research (FRCN-CCT-83028); Cancer Research UK; Cardionics; Cavadis B.V., Center for Medical Systems Biology; Center of Excellence in Genomics; CFI; CIHR; City of Kuopio; CNAMTS; Cohortes Sante´ TGIR; Contrat de Projets E´tat-Re´gion; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF-1333- 00124, DFF-1331-00730B); County Council of Dalarna; Dalarna University; Danish Council for Strategic Research; Danish Diabetes Academy; Danish Medical Research Council; Department of Health, UK; Development Fund from the University of Tartu (SP1GVARENG); Diabetes Hilfs- und Forschungsfonds Deutschland; Diabetes UK; Diabetes Research and Wellness Foundation Fellowship; Donald W. Reynolds Foundation; Dr Robert Pfleger-Stiftung; Dutch Brain Foundation; Dutch Diabetes Research Foundation; Dutch Inter University Cardiology Institute; Dutch Kidney Foundation (E033); Dutch Ministry of Justice; the DynaHEALTH action No. 633595, Economic Structure Enhancing Fund of the Dutch Government; Else Kro¨ner-Fresenius-Stiftung (2012_A147, P48/08//A11/08); Emil Aaltonen Foundation; Erasmus University Medical Center Rotterdam; Erasmus MC and Erasmus University Rotterdam; the Municipality of Rotterdam; Estonian Government (IUT20-60, IUT24-6); Estonian Research Roadmap through the Estonian Ministry of Education and Research (3.2.0304.11-0312); European Research Council (ERC Starting Grant and 323195:SZ-245 50371-GLUCOSEGENESFP7-IDEAS-ERC); European Regional Development Fund; European Science Foundation (EU/QLRT-2001-01254); European Commission (018947, 018996, 201668, 223004, 230374, 279143, 284167, 305739, BBMRI-LPC-313010, HEALTH-2011.2.4.2-2-EUMASCARA, HEALTH-2011-278913, HEALTH-2011-294713-EPLORE, HEALTH-F2- 2008-201865-GEFOS, HEALTH-F2-2013-601456, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550-HYPERGENES, HEALTH-F7-305507 HOMAGE, IMI/ 115006, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2004-005272, LSHM-CT-2006-037697, LSHM-CT-2007-037273, QLG1-CT-2002-00896, QLG2-CT2002-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ0103, 01ZZ0403, 01ZZ9603, 03IS2061A, 03ZIK012); Federal State of Mecklenburg-West Pomerania; Fe´de´ration Franc¸aise de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Fondation Leducq; Food Standards Agency; Foundation for Strategic Research; French Ministry of Research; FRSQ; Genetic Association Information Network (GAIN) of the Foundation for the NIH; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); GlaxoSmithKline; Greek General Secretary of Research and Technology; Go¨teborg Medical Society; Health and Safety Executive; Healthcare NHS Trust; Healthway; Western Australia; Heart Foundation of Northern Sweden; Helmholtz Zentrum Mu¨nchen—German Research Center for Environmental Health; Hjartavernd; Ingrid Thurings Foundation; INSERM; InterOmics (PB05 MIUR-CNR); INTERREG IV Oberrhein Program (A28); Interuniversity Cardiology Institute of the Netherlands (ICIN, 09.001); Italian Ministry of Health (ICS110.1/RF97.71); Italian Ministry of Economy and Finance (FaReBio di Qualita`); Marianne and Marcus Wallenberg Foundation; the Ministry of Health, Welfare and Sports, the Netherlands; J.D.E. and Catherine T, MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; KfH Stiftung Pra¨ventivmedizin e.V.; King's College London; Knut and Alice Wallenberg Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); La Fondation de France; Leenaards Foundation; Lilly; LMUinnovativ; Lundberg Foundation; Magnus Bergvall Foundation; MDEIE; Medical Research Council UK (G0000934, G0601966, G0700931, MC_U106179471, MC_UU_12019/1); MEKOS Laboratories; Merck Sante´; Ministry for Health, Welfare and Sports, The Netherlands; Ministry of Cultural Affairs of Mecklenburg-West Pomerania; Ministry of Economic Affairs, The Netherlands; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science, The Netherlands; Ministry of Science, Education and Sport in the Republic of Croatia (108-1080315-0302); MRC centre for Causal Analyses in Translational Epidemiology; MRC Human Genetics Unit; MRC-GlaxoSmithKline pilot programme (G0701863); MSD Stipend Diabetes; National Institute for Health Research; Netherlands Brain Foundation (F2013(1)-28); Netherlands CardioVascular Research Initiative (CVON2011-19); Netherlands Genomics Initiative (050-060-810); Netherlands Heart Foundation (2001 D 032, NHS2010B280); Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) (56-464- 14192, 60-60600-97-118, 100-001-004, 261-98-710, 400-05-717, 480-04-004, 480-05-003, 481-08-013, 904-61-090, 904-61-193, 911-11-025, 985-10-002, Addiction-31160008, BBMRI–NL 184.021.007, GB-MaGW 452-04-314, GB-MaGW 452-06-004, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MW 940-38-011, Middelgroot-911-09-032, NBIC/BioAssist/RK 2008.024, Spinozapremie 175.010.2003.005, 175.010.2007.006); NATURE COMMUNICATIONS | DOI:10.1038/ncomms14977 ARTICLE NATURE COMMUNICATIONS | 8:14977 | DOI:10.1038/ncomms14977 | www.nature.com/naturecommunications 13 Neuroscience Campus Amsterdam; NHS Foundation Trust; National Institutes of Health (1RC2MH089951, 1Z01HG000024, 24152, 263MD9164, 263MD821336, 2R01LM010098, 32100-2, 32122, 32108, 5K99HL130580-02, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, AG13196, CA047988, DA12854, DK56350, DK063491, DK078150, DK091718, DK100383, DK078616, ES10126, HG004790, HHSN268200625226C, HHSN268200800007C, HHSN268201200036C, HHSN268201500001I, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, HL043851, HL45670, HL080467, HL085144, HL087660, HL054457, HL119443, HL118305, HL071981, HL034594, HL126024, HL130114, KL2TR001109, MH66206, MH081802, N01AG12100, N01HC55015, N01HC55016, N01C55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, N01HG65403, N01WH22110, N02HL6-4278, N01-HC-25195, P01CA33619, R01HD057194, R01HD057194, R01AG023629, R01CA63, R01D004215701A, R01DK075787, R01DK062370, R01DK072193, R01DK075787, R01DK089256, R01HL53353, R01HL59367, R01HL086694, R01HL087641, R01HL087652, R01HL103612, R01HL105756, R01HL117078, R01HL120393, R03 AG046389, R37CA54281, RC2AG036495, RC4AG039029, RPPG040710371, RR20649, TW008288, TW05596, U01AG009740, U01CA98758, U01CA136792, U01DK062418, U01HG004402, U01HG004802, U01HG007376, U01HL080295, UL1RR025005, UL1TR000040, UL1TR000124, UL1TR001079, 2T32HL007055-36, T32GM074905, HG002651, HL084729, N01-HC25195, UM1CA182913); NIH, National Institute on Aging (Intramural funding, NO1-AG-1-2109); Northern Netherlands Collaboration of Provinces; Novartis Pharma; Novo Nordisk; Novo Nordisk Foundation; Nutricia Research Foundation (2016-T1); ONIVINS; Parnassia Bavo group; Pierre Fabre; Province of Groningen; Pa¨ivikki and Sakari Sohlberg Foundation; Påhlssons Foundation; Paavo Nurmi Foundation; Radboud Medical Center Nijmegen; Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Institute for Diseases in the Elderly; Research into Ageing; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Roche; Royal Society; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Government Health Directorates, Chief Scientist Office (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Socie´te´ Francophone du 358 Diabe`te; State of Bavaria; Stiftelsen fo¨r Gamla Tja¨narinnor; Stockholm County Council (560183, 592229); Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council; Stroke Association; Swedish Diabetes Association; Swedish Diabetes Foundation (2013-024); Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20120197, 20150711); Swedish Research Council (0593, 8691, 2012-1397, 2012-1727, and 2012-2215); Swedish Society for Medical Research; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 31003A-143914, 33CSCO-122661, 33CS30-139468, 33CS30-148401, 51RTP0_151019); Tampere Tuberculosis Foundation; Technology Foundation STW (11679); The Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community (G.0880.13, G.0881.13); The Great Wine Estates of the Margaret River Region of Western Australia; Timber Merchant Vilhelm Bangs Foundation; Topcon; Tore Nilsson Foundation; Torsten and Ragnar So¨derberg's Foundation; United States – Israel Binational Science Foundation (Grant 2011036), Umeå University; University Hospital of Regensburg; University of Groningen; University Medical Center Groningen; University of Michigan; University of Utrecht; Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) (b2011036); Velux Foundation; VU University's Institute for Health and Care Research; Va¨stra Go¨taland Foundation; Wellcome Trust (068545, 076113, 079895, 084723, 088869, WT064890, WT086596, WT098017, WT090532, WT098051, 098381); Wissenschaftsoffensive TMO; Yrjo¨ Jahnsson Foundation; and Åke Wiberg Foundation
