Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders

Background: The thyroid plays a key role in development and homeostasis, but it has been difficult to establish causality with diseases and phenotypic traits because of several potential confounders. Methods: To determine the causal effect of euthyroid function, we conducted a two-sample Mendelian randomization study of euthyroid thyrotropin (TSH) and free thyroxine (FT4) levels with respect to 2419 traits assessed in 337,199 individuals from UK Biobank. Additionally, we investigated the molecular differences between hypothyroidism and hyperthyroidism using genome-wide data. Results: After multiple testing correction, sixteen traits appear to be affected by genetically-determined euthyroid TSH, including multiple thyroid-related traits, e.g., hypothyroidism (p = 2.39 × 10−17), height (p = 2.76 × 10−10), body fat distribution (impedance of whole body, p = 4.43 × 10−8), pulse rate (p = 2.84 × 10−8), female infertility (p = 4.91 × 10−6), and hearing aid use (p = 7.10 × 10−5). Moreover, we found a consistent genetic correlation between hypothyroidism and hyperthyroidism (rg = 0.45, p = 5.45 × 10−6) with several immune pathways shared between these diseases. Two molecular pathways survived multiple testing correction for specificity to hyperthyroidism, JAK/STAT signaling (p = 1.02 × 10−6) and Rac guanyl-nucleotide exchange factor activity (p = 4.39 × 10−6). Conclusion: Our data shed new light on the inter-individual variability of euthyroid function and the molecular mechanisms of the two thyroid disorders investigated.