Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset
Williams, A. T.; Chen, J.; Coley, K.; Batini, C.; Izquierdo, A.; Packer, R.; Abner, E.; Shepherd, D. J.; Free, R. C.; Hollox, E. J.; Brunskill, N. J.; Ntalla, I.; Reeve, N.; Brightling, C. E.; Venn, L.; Adams, E.; Bee, C.; Wallace, S.; Pareek, M.; Hansell, A. L.; Esko, T.; Estonian Biobank Research Team, ; Hennah, W.; Rao, B. S.; Dudbridge, F.; Wain, L. V.; Shrine, N.; Tobin, M. D.; John, C.
Show abstract
Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used 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.
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