GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Zhou, Wei, Brumpton, Ben, Kabil, Omer, Gudmundsson, Julius, Thorleifsson, Gudmar, Weinstock, Josh, Zawistowski, Matthew, Nielsen, Jonas B., Chaker, Layal, Medici, Marco, Teumer, Alexander, Naitza, Silvia, Sanna, Serena, Schultheiss, Ulla T., Cappola, Anne, Karjalainen, Juha, Kurki, Mitja, Oneka, Morgan, Taylor, Peter ORCID: https://orcid.org/0000-0002-3436-422X, Fritsche, Lars G., Graham, Sarah E., Wolford, Brooke N., Overton, William, Rasheed, Humaira, Haug, Eirin B., Gabrielsen, Maiken E., Skogholt, Anne Heidi, Surakka, Ida, Davey Smith, George, Pandit, Anita, Roychowdhury, Tanmoy, Hornsby, Whitney E., Jonasson, Jon G., Senter, Leigha, Liyanarachchi, Sandya, Ringel, Matthew D., Xu, Li, Kiemeney, Lambertus A., He, Huiling, Netea-Maier, Romana T., Mayordomo, Jose I., Plantinga, Theo S., Hrafnkelsson, Jon, Hjartarson, Hannes, Sturgis, Erich M., Palotie, Aarno, Daly, Mark, Citterio, Cintia E., Arvan, Peter, Brummett, Chad M., Boehnke, Michael, de la Chapelle, Albert, Stefansson, Kari, Hveem, Kristian, Willer, Cristen J. and Åsvold, Bjørn Olav 2020. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nature Communications 11 , 3981. s41467-020-17718-z

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Abstract

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	Correction published at https://doi.org/10.1038/s41467-021-27675-w
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	26 January 2022
Date of Acceptance:	8 June 2020
Last Modified:	11 Oct 2023 21:27
URI:	https://orca.cardiff.ac.uk/id/eprint/146959

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