PLoS Genetics (Jan 2013)

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

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

DOI
https://doi.org/10.1371/journal.pgen.1003266
Journal volume & issue
Vol. 9, no. 2
p. e1003266

Abstract

Read online

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.