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

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posted on 2024-06-21, 13:47 authored by Alexander T Williams, Jing Chen, Kayesha Coley, Chiara Batini, Abril Izquierdo, Richard PackerRichard Packer, Erik Abner, Stavroula Kanoni, David J Shepherd, Robert FreeRobert Free, Ed HolloxEd Hollox, Nigel J Brunskill, Ioanna Ntalla, Nicola Reeve, Christopher BrightlingChristopher Brightling, Laura Venn, Emma Adams, Catherine Bee, Susan E Wallace, Manish Pareek, Anna L Hansell, Tõnu Esko, Daniel Stow, Benjamin M Jacobs, David A van Heel, William Hennah, Balasubramanya S Rao, Frank DudbridgeFrank Dudbridge, Louise V Wain, Nick Shrine, Martin D Tobin, Catherine John

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.

History

Author affiliation

College of Life Sciences College of Science & Engineering Cardiovascular Sciences Genetics & Genome Biology Population Health Sciences Respiratory Sciences Comp' & Math' Sciences

Version

  • VoR (Version of Record)

Published in

Nature Communications

Volume

14

Issue

1

Pagination

6713

Publisher

Springer Science and Business Media LLC

issn

2041-1723

eissn

2041-1723

Copyright date

2024

Available date

2024-06-21

Spatial coverage

England

Language

en

Deposited by

Professor Ed Hollox

Deposit date

2024-06-17

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