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.
Highlights
Through the production of thyroid hormone (TH), the thyroid is essential for normal development, growth and metabolism of virtually all human tissues
To identify common genetic variants associated with the highly heritable markers of thyroid function, thyroid stimulating hormone (TSH) and free T4 (FT4), we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function
Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH and FT4 levels
Summary
Through the production of thyroid hormone (TH), the thyroid is essential for normal development, growth and metabolism of virtually all human tissues. Low thyroid function (i.e., hypothyroidism) can lead to weight gain, high cholesterol, cognitive dysfunction, depression, and cold intolerance, whereas hyperthyroidism may result in weight loss, tachycardia, atrial fibrillation, and osteoporosis. The thyroid gland secretes predominantly the pro-hormone thyroxine (T4), which is converted into the active form triiodothyronine (T3) in peripheral tissues. Low levels of serum TH in hypothyroidism result in an increased release of thyroid stimulating hormone (TSH) by the pituitary, under the influence of hypothalamic thyrotropin releasing hormone (TRH) [5]. TSH, a key regulator of thyroid function, stimulates the synthesis and secretion of TH by the thyroid. When circulating TH levels are high, as in hyperthyroidism, TRH and TSH synthesis and secretion are inhibited
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