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A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function
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 change...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567175/ https://www.ncbi.nlm.nih.gov/pubmed/23408906 http://dx.doi.org/10.1371/journal.pgen.1003266 |
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author | Porcu, Eleonora Medici, Marco Pistis, Giorgio Volpato, Claudia B. Wilson, Scott G. Cappola, Anne R. Bos, Steffan D. Deelen, Joris den Heijer, Martin Freathy, Rachel M. Lahti, Jari Liu, Chunyu Lopez, Lorna M. Nolte, Ilja M. O'Connell, Jeffrey R. Tanaka, Toshiko Trompet, Stella Arnold, Alice Bandinelli, Stefania Beekman, Marian Böhringer, Stefan Brown, Suzanne J. Buckley, Brendan M. Camaschella, Clara de Craen, Anton J. M. Davies, Gail de Visser, Marieke C. H. Ford, Ian Forsen, Tom Frayling, Timothy M. Fugazzola, Laura Gögele, Martin Hattersley, Andrew T. Hermus, Ad R. Hofman, Albert Houwing-Duistermaat, Jeanine J. Jensen, Richard A. Kajantie, Eero Kloppenburg, Margreet Lim, Ee M. Masciullo, Corrado Mariotti, Stefano Minelli, Cosetta Mitchell, Braxton D. Nagaraja, Ramaiah Netea-Maier, Romana T. Palotie, Aarno Persani, Luca Piras, Maria G. Psaty, Bruce M. Räikkönen, Katri Richards, J. Brent Rivadeneira, Fernando Sala, Cinzia Sabra, Mona M. Sattar, Naveed Shields, Beverley M. Soranzo, Nicole Starr, John M. Stott, David J. Sweep, Fred C. G. J. Usala, Gianluca van der Klauw, Melanie M. van Heemst, Diana van Mullem, Alies H.Vermeulen, Sita Visser, W. Edward Walsh, John P. Westendorp, Rudi G. J. Widen, Elisabeth Zhai, Guangju Cucca, Francesco Deary, Ian J. Eriksson, Johan G. Ferrucci, Luigi Fox, Caroline S. Jukema, J. Wouter Kiemeney, Lambertus A. Pramstaller, Peter P. Schlessinger, David Shuldiner, Alan R. Slagboom, Eline P. Uitterlinden, André G. Vaidya, Bijay Visser, Theo J. Wolffenbuttel, Bruce H. R. Meulenbelt, Ingrid Rotter, Jerome I. Spector, Tim D. Hicks, Andrew A. Toniolo, Daniela Sanna, Serena Peeters, Robin P. Naitza, Silvia |
author_facet | Porcu, Eleonora Medici, Marco Pistis, Giorgio Volpato, Claudia B. Wilson, Scott G. Cappola, Anne R. Bos, Steffan D. Deelen, Joris den Heijer, Martin Freathy, Rachel M. Lahti, Jari Liu, Chunyu Lopez, Lorna M. Nolte, Ilja M. O'Connell, Jeffrey R. Tanaka, Toshiko Trompet, Stella Arnold, Alice Bandinelli, Stefania Beekman, Marian Böhringer, Stefan Brown, Suzanne J. Buckley, Brendan M. Camaschella, Clara de Craen, Anton J. M. Davies, Gail de Visser, Marieke C. H. Ford, Ian Forsen, Tom Frayling, Timothy M. Fugazzola, Laura Gögele, Martin Hattersley, Andrew T. Hermus, Ad R. Hofman, Albert Houwing-Duistermaat, Jeanine J. Jensen, Richard A. Kajantie, Eero Kloppenburg, Margreet Lim, Ee M. Masciullo, Corrado Mariotti, Stefano Minelli, Cosetta Mitchell, Braxton D. Nagaraja, Ramaiah Netea-Maier, Romana T. Palotie, Aarno Persani, Luca Piras, Maria G. Psaty, Bruce M. Räikkönen, Katri Richards, J. Brent Rivadeneira, Fernando Sala, Cinzia Sabra, Mona M. Sattar, Naveed Shields, Beverley M. Soranzo, Nicole Starr, John M. Stott, David J. Sweep, Fred C. G. J. Usala, Gianluca van der Klauw, Melanie M. van Heemst, Diana van Mullem, Alies H.Vermeulen, Sita Visser, W. Edward Walsh, John P. Westendorp, Rudi G. J. Widen, Elisabeth Zhai, Guangju Cucca, Francesco Deary, Ian J. Eriksson, Johan G. Ferrucci, Luigi Fox, Caroline S. Jukema, J. Wouter Kiemeney, Lambertus A. Pramstaller, Peter P. Schlessinger, David Shuldiner, Alan R. Slagboom, Eline P. Uitterlinden, André G. Vaidya, Bijay Visser, Theo J. Wolffenbuttel, Bruce H. R. Meulenbelt, Ingrid Rotter, Jerome I. Spector, Tim D. Hicks, Andrew A. Toniolo, Daniela Sanna, Serena Peeters, Robin P. Naitza, Silvia |
author_sort | Porcu, Eleonora |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3567175 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35671752013-02-13 A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function Porcu, Eleonora Medici, Marco Pistis, Giorgio Volpato, Claudia B. Wilson, Scott G. Cappola, Anne R. Bos, Steffan D. Deelen, Joris den Heijer, Martin Freathy, Rachel M. Lahti, Jari Liu, Chunyu Lopez, Lorna M. Nolte, Ilja M. O'Connell, Jeffrey R. Tanaka, Toshiko Trompet, Stella Arnold, Alice Bandinelli, Stefania Beekman, Marian Böhringer, Stefan Brown, Suzanne J. Buckley, Brendan M. Camaschella, Clara de Craen, Anton J. M. Davies, Gail de Visser, Marieke C. H. Ford, Ian Forsen, Tom Frayling, Timothy M. Fugazzola, Laura Gögele, Martin Hattersley, Andrew T. Hermus, Ad R. Hofman, Albert Houwing-Duistermaat, Jeanine J. Jensen, Richard A. Kajantie, Eero Kloppenburg, Margreet Lim, Ee M. Masciullo, Corrado Mariotti, Stefano Minelli, Cosetta Mitchell, Braxton D. Nagaraja, Ramaiah Netea-Maier, Romana T. Palotie, Aarno Persani, Luca Piras, Maria G. Psaty, Bruce M. Räikkönen, Katri Richards, J. Brent Rivadeneira, Fernando Sala, Cinzia Sabra, Mona M. Sattar, Naveed Shields, Beverley M. Soranzo, Nicole Starr, John M. Stott, David J. Sweep, Fred C. G. J. Usala, Gianluca van der Klauw, Melanie M. van Heemst, Diana van Mullem, Alies H.Vermeulen, Sita Visser, W. Edward Walsh, John P. Westendorp, Rudi G. J. Widen, Elisabeth Zhai, Guangju Cucca, Francesco Deary, Ian J. Eriksson, Johan G. Ferrucci, Luigi Fox, Caroline S. Jukema, J. Wouter Kiemeney, Lambertus A. Pramstaller, Peter P. Schlessinger, David Shuldiner, Alan R. Slagboom, Eline P. Uitterlinden, André G. Vaidya, Bijay Visser, Theo J. Wolffenbuttel, Bruce H. R. Meulenbelt, Ingrid Rotter, Jerome I. Spector, Tim D. Hicks, Andrew A. Toniolo, Daniela Sanna, Serena Peeters, Robin P. Naitza, Silvia PLoS Genet Research Article 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. Public Library of Science 2013-02-07 /pmc/articles/PMC3567175/ /pubmed/23408906 http://dx.doi.org/10.1371/journal.pgen.1003266 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Porcu, Eleonora Medici, Marco Pistis, Giorgio Volpato, Claudia B. Wilson, Scott G. Cappola, Anne R. Bos, Steffan D. Deelen, Joris den Heijer, Martin Freathy, Rachel M. Lahti, Jari Liu, Chunyu Lopez, Lorna M. Nolte, Ilja M. O'Connell, Jeffrey R. Tanaka, Toshiko Trompet, Stella Arnold, Alice Bandinelli, Stefania Beekman, Marian Böhringer, Stefan Brown, Suzanne J. Buckley, Brendan M. Camaschella, Clara de Craen, Anton J. M. Davies, Gail de Visser, Marieke C. H. Ford, Ian Forsen, Tom Frayling, Timothy M. Fugazzola, Laura Gögele, Martin Hattersley, Andrew T. Hermus, Ad R. Hofman, Albert Houwing-Duistermaat, Jeanine J. Jensen, Richard A. Kajantie, Eero Kloppenburg, Margreet Lim, Ee M. Masciullo, Corrado Mariotti, Stefano Minelli, Cosetta Mitchell, Braxton D. Nagaraja, Ramaiah Netea-Maier, Romana T. Palotie, Aarno Persani, Luca Piras, Maria G. Psaty, Bruce M. Räikkönen, Katri Richards, J. Brent Rivadeneira, Fernando Sala, Cinzia Sabra, Mona M. Sattar, Naveed Shields, Beverley M. Soranzo, Nicole Starr, John M. Stott, David J. Sweep, Fred C. G. J. Usala, Gianluca van der Klauw, Melanie M. van Heemst, Diana van Mullem, Alies H.Vermeulen, Sita Visser, W. Edward Walsh, John P. Westendorp, Rudi G. J. Widen, Elisabeth Zhai, Guangju Cucca, Francesco Deary, Ian J. Eriksson, Johan G. Ferrucci, Luigi Fox, Caroline S. Jukema, J. Wouter Kiemeney, Lambertus A. Pramstaller, Peter P. Schlessinger, David Shuldiner, Alan R. Slagboom, Eline P. Uitterlinden, André G. Vaidya, Bijay Visser, Theo J. Wolffenbuttel, Bruce H. R. Meulenbelt, Ingrid Rotter, Jerome I. Spector, Tim D. Hicks, Andrew A. Toniolo, Daniela Sanna, Serena Peeters, Robin P. Naitza, Silvia A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function |
title | A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function |
title_full | A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function |
title_fullStr | A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function |
title_full_unstemmed | A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function |
title_short | A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function |
title_sort | meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567175/ https://www.ncbi.nlm.nih.gov/pubmed/23408906 http://dx.doi.org/10.1371/journal.pgen.1003266 |
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metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT psatybrucem metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT raikkonenkatri metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT richardsjbrent metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT rivadeneirafernando metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT salacinzia metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT sabramonam metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT sattarnaveed 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metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT vanheemstdiana metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT vanmullemalies metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT hvermeulensita metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT visserwedward metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT walshjohnp metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT westendorprudigj metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT widenelisabeth 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metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT kiemeneylambertusa metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT pramstallerpeterp metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT schlessingerdavid metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT shuldineralanr metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT slagboomelinep metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT uitterlindenandreg metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT vaidyabijay 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metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT sannaserena metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT peetersrobinp metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT naitzasilvia metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction |