Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease

• Published in: Nature communications Vol. 14; no. 1; p. 6713
• Main Authors: Williams, Alexander T., Chen, Jing, Coley, Kayesha, Batini, Chiara, Izquierdo, Abril, Packer, Richard, Abner, Erik, Kanoni, Stavroula, Shepherd, David J., Free, Robert C., Hollox, Edward J., Brunskill, Nigel J., Ntalla, Ioanna, Reeve, Nicola, Brightling, Christopher E., Venn, Laura, Adams, Emma, Bee, Catherine, Wallace, Susan E., Pareek, Manish, Hansell, Anna L., Esko, Tõnu, Stow, Daniel, Jacobs, Benjamin M., van Heel, David A., Hennah, William, Rao, Balasubramanya S., Dudbridge, Frank, Wain, Louise V., Shrine, Nick, Tobin, Martin D., John, Catherine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/43; 45; 45/43; 631/208/205/2138; 692/163/2743/1841; 692/308/2056; Age; Electronic health records; Electronic medical records; Gene mapping; Genes; Genome-wide association studies; Genome-Wide Association Study; Genomes; Hormones; Humanities and Social Sciences; Humans; Hyperthyroidism; Hyperthyroidism - genetics; Hypothyroidism; Hypothyroidism - genetics; Morbidity; multidisciplinary; Perturbation; Physiology; Science; Science (multidisciplinary); Thyroid; Thyroid cancer; Thyroid diseases; Thyroid Diseases - genetics; Thyroid hormones; Thyroid-stimulating hormone; Thyrotropin - genetics; Thyroxine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42284-5

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases. Thyroid hormones play a critical role in regulation of multiple physiological functions. Here the authors via meta-analyses and detailed variant-to-gene mapping strategies implicate novel genes, pathways and associations for thyroid function and disease.