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

Alexander T. Williams (), Jing Chen, Kayesha Coley, Chiara Batini, Abril Izquierdo, Richard Packer, Erik Abner, Stavroula Kanoni, David J. Shepherd, Robert C. Free, Edward J. Hollox, Nigel J. Brunskill, Ioanna Ntalla, Nicola Reeve, Christopher E. 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 Dudbridge, Louise V. Wain, Nick Shrine, Martin D. Tobin and Catherine John ()
Additional contact information
Alexander T. Williams: University of Leicester
Jing Chen: University of Leicester
Kayesha Coley: University of Leicester
Chiara Batini: University of Leicester
Abril Izquierdo: University of Leicester
Richard Packer: University of Leicester
Erik Abner: University of Tartu
Stavroula Kanoni: Queen Mary University of London
David J. Shepherd: University of Leicester
Robert C. Free: University Hospitals of Leicester NHS Trust, Infirmary Square
Edward J. Hollox: University of Leicester
Nigel J. Brunskill: Department of Cardiovascular Sciences, University of Leicester
Ioanna Ntalla: University of Leicester
Nicola Reeve: University of Leicester
Christopher E. Brightling: University Hospitals of Leicester NHS Trust, Infirmary Square
Laura Venn: University of Leicester
Emma Adams: University of Leicester
Catherine Bee: University of Leicester
Susan E. Wallace: University of Leicester
Manish Pareek: University Hospitals of Leicester NHS Trust, Infirmary Square
Anna L. Hansell: University of Leicester
Tõnu Esko: University of Tartu
Daniel Stow: Queen Mary University of London
Benjamin M. Jacobs: Queen Mary University of London
David A. van Heel: Queen Mary University of London
William Hennah: Orion Pharma
Balasubramanya S. Rao: Orion Pharma
Frank Dudbridge: University of Leicester
Louise V. Wain: University of Leicester
Nick Shrine: University of Leicester
Martin D. Tobin: University of Leicester
Catherine John: University of Leicester

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42284-5

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DOI: 10.1038/s41467-023-42284-5

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