Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
PLoS Genet. 2013;9(2):e1003266. doi: 10.1371/journal.pgen.1003266. Epub 2013 Feb 7.
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.
甲状腺激素对正常新陈代谢和发育至关重要，甲状腺功能的明显异常会导致常见的内分泌紊乱，影响大约 10%的个体在其一生中。此外，即使甲状腺功能有轻微改变，也与体重变化、心房颤动、骨质疏松症和精神疾病有关。为了确定甲状腺功能的潜在新变体，我们对血清促甲状腺激素 (TSH) 和游离甲状腺素 (FT4) 的高度遗传功能标志物的全基因组关联研究进行了大型荟萃分析，分别在多达 26420 名和 17520 名甲状腺功能正常的受试者中进行。在这里，我们报告了 26 个独立的关联，包括 TSH 的几个新位点（PDE10A、VEGFA、IGFBP5、NFIA、SOX9、PRDM11、FGF7、INSR、ABO、MIR1179、NRG1、MBIP、ITPK1、SASH1、GLIS3）和 FT4（LHX3、FOXE1、AADAT、NETO1/FBXO15、LPCAT2/CAPNS2）。值得注意的是，尽管下丘脑-垂体-甲状腺轴对其循环水平进行反馈调节，但在 TSH 和 FT4 相关信号之间仅检测到有限的重叠。报告的五个位点（PDE8B、PDE10A、MAF/LOC440389、NETO1/FBXO15 和 LPCAT2/CAPNS2）表现出强烈的性别特异性差异，这为甲状腺功能和相关病理的已知性别二态性提供了线索。重要的是，TSH 相关基因座不仅对正常范围内的变异有贡献，而且对参考范围内的 TSH 值也有贡献，这表明它们可能与甲状腺功能障碍有关。总体而言，我们的研究结果分别解释了 TSH 和 FT4 总变异的 5.64%和 2.30%，并提高了对下丘脑-垂体-甲状腺轴功能调节以及遗传变异对甲状腺功能减退或甲状腺功能亢进的影响的认识。
