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

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. and John, Catherine 2023. Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease. Nature Communications 14 (1) , 6713. 10.1038/s41467-023-42284-5

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	25 October 2023
Date of Acceptance:	5 October 2023
Last Modified:	25 Oct 2023 09:00
URI:	https://orca.cardiff.ac.uk/id/eprint/163493

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