ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This genome-wide association study (GWAS) meta-analysis of 271,040 European participants investigated the genetic determinants of thyroid function, including reference range serum TSH, FT4, free and total T3, proxies for metabolism (T3/FT4 ratio), as well as dichotomized high and low TSH levels. It identified 259 independent associations for TSH, 85 for FT4, and novel associations for thyroid hormone (TH) metabolism (T3/FT4 ratio). Genetic variants explained 14.1%, 6.0%, and 9.5% of TSH, FT4, and total T3 concentrations, respectively. Polygenic risk score and Mendelian randomization analyses showed that genetically determined variations in thyroid function have significant implications for cardiovascular diseases, autoimmune disorders, and cancer risk. Additionally, novel loci linked to TH transport, synthesis, and metabolism were identified.

In contrast to the study by Williams et al [1], this large-scale GWAS not only investigated genetic factors influencing TSH levels within the reference interval, but also reference range free FT4, FT3 and total T3, proxies for metabolism, and dichotomized high and low TSH levels. This provides new insights into the genetic regulation of thyroid function, as well as into TH transport, synthesis, and metabolism.

Reference: 1. Alexander T Williams et al. Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease. Nat Commun. 2023 Oct 23;14(1):6713. doi: 10.1038/s41467-023-42284-5. PMID: 37872160