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

Wei Zhou*, Ben M Brumpton, Omer Kabil, Julius Gudmundsson, Gudmar Thorleifsson, Josh Weinstock, Matthew Zawistowski, Jonas B Nielsen, Layal Chaker, Marco Medici, Alexander Teumer, Silvia Naitza, Serena Sanna, Ulla Schultheiss, Anne Cappola, Juha Karjalainen, Mitja I. Kurki, Morgan Oneka, Peter Taylor, Lars G FritscheSarah Graham, Brooke Wolford, William Overton, Humaira Rasheed, Eirin B Haug, Maiken Gabrielsen, Anne Heidi Skogholt, Ida Surakka, George Davey Smith, Anita Pandit, Tanmoy Roychowdhury, Whitney Hornsby, Jon G. Jonasson, Leigha Senter, Sandya Liyanarachchi, Matthew Ringel, LI Xu, Lambertus A Kiemeney, Huiling He, Romana Netea-Maier, José I. Mayordomo, Theo Plantinga, Jon Hrafnkelsson, Hannes Hjartarson, Erich Sturgis, Aarno Palotie, Mark Daly, Cintia Citterio, Peter Arvan, Chad M Brummett, Michael Boehnke, Albert de la Chapelle, Kari Stefansson, Kristian Hveem, Cristen J Willer, Bjorn O Asvold*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 novel. 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 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.
Original languageEnglish
Article number3981
Number of pages13
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 7 Aug 2020

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