McCarthy, Mark I. and Porcu, Eleonora and Medici, Marco and Pistis, Giorgio and Volpato, Claudia B. and Wilson, Scott G. and Cappola, Anne R. and Bos, Steffan D. and Deelen, Joris and den Heijer, Martin and Freathy, Rachel M. and Lahti, Jari and Liu, Chunyu and Lopez, Lorna M. and Nolte, Ilja M. and O'Connell, Jeffrey R. and Tanaka, Toshiko and Trompet, Stella and Arnold, Alice and Bandinelli, Stefania and Beekman, Marian and Böhringer, Stefan and Brown, Suzanne J. and Buckley, Brendan M. and Camaschella, Clara and de Craen, Anton J. M. and Davies, Gail and de Visser, Marieke C. H. and Ford, Ian and Forsen, Tom and Frayling, Timothy M. and Fugazzola, Laura and Gögele, Martin and Hattersley, Andrew T. and Hermus, Ad R. and Hofman, Albert and Houwing-Duistermaat, Jeanine J. and Jensen, Richard A. and Kajantie, Eero and Kloppenburg, Margreet and Lim, Ee M. and Masciullo, Corrado and Mariotti, Stefano and Minelli, Cosetta and Mitchell, Braxton D. and Nagaraja, Ramaiah and Netea-Maier, Romana T. and Palotie, Aarno and Persani, Luca and Piras, Maria G. and Psaty, Bruce M. and Räikkönen, Katri and Richards, J. Brent and Rivadeneira, Fernando and Sala, Cinzia and Sabra, Mona M. and Sattar, Naveed and Shields, Beverley M. and Soranzo, Nicole and Starr, John M. and Stott, David J. and Sweep, Fred C. G. J. and Usala, Gianluca and van der Klauw, Melanie M. and van Heemst, Diana and van Mullem, Alies and H.Vermeulen, Sita and Visser, W. Edward and Walsh, John P. and Westendorp, Rudi G. J. and Widen, Elisabeth and Zhai, Guangju and Cucca, Francesco and Deary, Ian J. and Eriksson, Johan G. and Ferrucci, Luigi and Fox, Caroline S. and Jukema, J. Wouter and Kiemeney, Lambertus A. and Pramstaller, Peter P. and Schlessinger, David and Shuldiner, Alan R. and Slagboom, Eline P. and Uitterlinden, André G. and Vaidya, Bijay and Visser, Theo J. and Wolffenbuttel, Bruce H. R. and Meulenbelt, Ingrid and Rotter, Jerome I. and Spector, Tim D. and Hicks, Andrew A. and Toniolo, Daniela and Sanna, Serena and Peeters, Robin P. and Naitza, Silvia (2013) A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function. PLoS Genetics, 9 (2). e1003266. ISSN 1553-7404

Preview

Download (1MB) | Preview

Abstract

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.

Item Type:	Article
Keywords:	Meta-Analysis; Thyroid-Related; Traits; Reveals; Novel Loci; Gender-Specific Differences; Regulation; Thyroid Function;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17257
Identification Number:	https://doi.org/10.1371/journal.pgen.1003266
Depositing User:	Lorna Lopez
Date Deposited:	29 May 2023 16:01
Journal or Publication Title:	PLoS Genetics
Publisher:	Public Library of Science
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

Repository Staff Only(login required)

Item control page

Downloads

Origin of downloads