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

McCarthy, M.I. et al. (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. (doi:10.1371/journal.pgen.1003266)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stott, Professor David J and Ford, Professor Ian and Sattar, Professor Naveed
Authors: McCarthy, M.I., Porcu, E., Medici, M., Pistis, G., Volpato, C.B., Wilson, S.G., Cappola, A.R., Bos, S.D., Deelen, J., den Heijer, M., Freathy, R.M., Lahti, J., Liu, C., Lopez, L.M., Nolte, I.M., O'Connell, J.R., Tanaka, T., Trompet, S., Arnold, A., Bandinelli, S., Beekman, M., Böhringer, S., Brown, S.J., Buckley, B.M., Camaschella, C., de Craen, A.J.M., Davies, G., de Visser, M.C.H., Ford, I., Forsen, T., Frayling, T.M., Fugazzola, L., Gögele, M., Hattersley, A.T., Hermus, A.R., Hofman, A., Houwing-Duistermaat, J.J., Jensen, R.A., Kajantie, E., Kloppenburg, M., Lim, E.M., Masciullo, C., Mariotti, S., Minelli, C., Mitchell, B.D., Nagaraja, R., Netea-Maier, R.T., Palotie, A., Persani, L., Piras, M.G., Psaty, B.M., Räikkönen, K., Richards, J.B., Rivadeneira, F., Sala, C., Sabra, M.M., Sattar, N., Shields, B.M., Soranzo, N., Starr, J.M., Stott, D.J., Sweep, F.C.G.J., Usala, G., van der Klauw, M.M., van Heemst, D., van Mullem, A., H.Vermeulen, S., Visser, W.E., Walsh, J.P., Westendorp, R.G.J., Widen, E., Zhai, G., Cucca, F., Deary, I.J., Eriksson, J.G., Ferrucci, L., Fox, C.S., Jukema, J.W., Kiemeney, L.A., Pramstaller, P.P., Schlessinger, D., Shuldiner, A.R., Slagboom, E.P., Uitterlinden, A.G., Vaidya, B., Visser, T.J., Wolffenbuttel, B.H.R., Meulenbelt, I., Rotter, J.I., Spector, T.D., Hicks, A.A., Toniolo, D., Sanna, S., Peeters, R.P., and Naitza, S.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in PLoS Genetics 9(2):e1003266
Publisher Policy:Reproduced under a Creative Commons License

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