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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
Authors: Porcu, E
Medici, M
Pistis, G
Volpato, CB
Wilson, SG
Cappola, AR
Bos, SD
Deelen, J
Den Heijer, M
Freathy, RM
Lahti, J
Liu, C
Lopez, LM
Nolte, IM
O'Connell, JR
Tanaka, T
Trompet, S
Arnold, A
Bandinelli, S
Beekman, M
Böhringer, S
Brown, SJ
Buckley, BM
Camaschella, C
De Craen, AJ
Davies, G
De Visser, MC
Ford, I
Forsen, T
Frayling, TM
Fugazzola, L
Gögele, M
Hattersley, AT
Hermus, AR
Hofman, A
Houwing-Duistermaat, JJ
Jensen, RA
Kajantie, E
Kloppenburg, M
Lim, EM
Masciullo, C
Mariotti, S
Minelli, C
Mitchell, BD
Nagaraja, R
Netea-Maier, RT
Palotie, A
Persani, L
Piras, MG
Psaty, BM
Räikkönen, K
Richards, JB
Rivadeneira, F
Sala, C
Sabra, MM
Sattar, N
Shields, BM
Soranzo, N
Starr, JM
Stott, DJ
Sweep, FC
Usala, G
Van der Klauw, MM
Van Heemst, D
Van Mullem, A
Vermeulen, SH
Visser, WE
Walsh, JP
Westendorp, RG
Widen, E
Zhai, G
Cucca, F
Deary, IJ
Eriksson, JG
Ferrucci, L
Fox, CS
Jukema, JW
Kiemeney, LA
Pramstaller, PP
Schlessinger, D
Shuldiner, AR
Slagboom, EP
Uitterlinden, AG
Vaidya, B
Visser, TJ
Wolffenbuttel, BH
Meulenbelt, I
Rotter, JI
Spector, TD
Hicks, AA
Toniolo, D
Sanna, S
Peeters, RP
Naitza, S
Item Type: Journal Article
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.
Issue Date: 7-Feb-2013
Date of Acceptance: 12-Nov-2012
URI: http://hdl.handle.net/10044/1/34675
DOI: https://dx.doi.org/10.1371/journal.pgen.1003266
ISSN: 1553-7390
Publisher: Public Library of Science
Journal / Book Title: PLOS Genetics
Volume: 9
Issue: 2
Copyright Statement: 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.
Keywords: Female
Genome-Wide Association Study
Humans
Hyperthyroidism
Hypothyroidism
Male
Phenotype
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Sex Characteristics
Signal Transduction
Thyroid Gland
Thyrotropin
Thyroxine
Developmental Biology
Genetics
Publication Status: Published
Conference Place: United States
Article Number: e1003266
Appears in Collections:Infectious Disease Epidemiology
National Heart and Lung Institute
Faculty of Medicine



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