Multi-Trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Abstract

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.Thyroid function tests are among the most frequently ordered biochemical tests worldwide to assess thyroid dysfunction, a common disorder with a prevalence of ~5% in the general population 1 . Thyroid hormones (TH) play a key role in the development and function of virtually all tissues during lifespan in humans 2,3 . Thyroid function is narrowly regulated by the hypothalamus-pituitary-thyroid axis 4 . The hypothalamus produces thyrotropin-releasing hormone (TRH) which acts on the pituitary gland to secrete thyrotropin (thyroid-stimulating hormone, TSH). The pituitary, in turn, stimulates the thyroid gland to produce and release TH, i.e. the prohormone thyroxine (T4) and the active hormone triiodothyronine (T3). The majority of T4 is converted intracellularly to T3 by deiodinases in peripheral tissues. T3 subsequently binds to the nuclear receptor regulating transcription of target genes. The hypothalamus-pituitary-thyroid axis is regulated by a negative feedback loop, resulting in a reciprocal physiological relationship between TSH and TH levels, aimed at maintaining adequate TH levels throughout life 5,6 (Fig. 1a).Thyroid function is assessed by measuring circulating TSH and free T4 (FT4) levels, with, in most cases, high TSH indicating hypothyroidism and low TSH indicating hyperthyroidism. FT4 levels are decreased in overt hypothyroidism, increased in overt hyperthyroidism, and in the reference range in subclinical hypo-and hyperthyroidism. To safely guide thyroid function, reference range TSH and FT4 concentrations are used. In the last decade, it has become clear that not only overt but also subclinical hypo-and hyperthyroidism are associated with several adverse clinical outcomes, including atrial fibrillation, coronary heart disease, stroke, and mortality 7...