Nature Communications (Oct 2023)
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,
- Estonian Biobank Research Team,
- Daniel Stow,
- Benjamin M. Jacobs,
- David A. van Heel,
- Genes & Health Research Team,
- William Hennah,
- Balasubramanya S. Rao,
- Frank Dudbridge,
- Louise V. Wain,
- Nick Shrine,
- Martin D. Tobin,
- Catherine John
Affiliations
- Alexander T. Williams
- Department of Population Health Sciences, University of Leicester
- Jing Chen
- Department of Population Health Sciences, University of Leicester
- Kayesha Coley
- Department of Population Health Sciences, University of Leicester
- Chiara Batini
- Department of Population Health Sciences, University of Leicester
- Abril Izquierdo
- Department of Population Health Sciences, University of Leicester
- Richard Packer
- Department of Population Health Sciences, University of Leicester
- Erik Abner
- Estonian Genome Center, Institute of Genomics, University of Tartu
- Stavroula Kanoni
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- David J. Shepherd
- Department of Population Health Sciences, University of Leicester
- Robert C. Free
- University Hospitals of Leicester NHS Trust, Infirmary Square
- Edward J. Hollox
- Department of Genetics and Genome Biology, University of Leicester
- Nigel J. Brunskill
- Department of Cardiovascular Sciences, University of Leicester
- Ioanna Ntalla
- Department of Population Health Sciences, University of Leicester
- Nicola Reeve
- Department of Population Health Sciences, University of Leicester
- Christopher E. Brightling
- University Hospitals of Leicester NHS Trust, Infirmary Square
- Laura Venn
- Department of Population Health Sciences, University of Leicester
- Emma Adams
- Department of Population Health Sciences, University of Leicester
- Catherine Bee
- Department of Population Health Sciences, University of Leicester
- Susan E. Wallace
- Department of Population Health Sciences, University of Leicester
- Manish Pareek
- University Hospitals of Leicester NHS Trust, Infirmary Square
- Anna L. Hansell
- Department of Population Health Sciences, University of Leicester
- Tõnu Esko
- Estonian Genome Center, Institute of Genomics, University of Tartu
- Estonian Biobank Research Team
- Daniel Stow
- Wolfson Institute of Population Health, Queen Mary University of London
- Benjamin M. Jacobs
- Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London
- David A. van Heel
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- Genes & Health Research Team
- William Hennah
- Orion Pharma
- Balasubramanya S. Rao
- Orion Pharma
- Frank Dudbridge
- Department of Population Health Sciences, University of Leicester
- Louise V. Wain
- Department of Population Health Sciences, University of Leicester
- Nick Shrine
- Department of Population Health Sciences, University of Leicester
- Martin D. Tobin
- Department of Population Health Sciences, University of Leicester
- Catherine John
- Department of Population Health Sciences, University of Leicester
- DOI
- https://doi.org/10.1038/s41467-023-42284-5
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
