GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
Zhou, Wei; Brumpton, Ben Michael; Kabil, Omer; Gudmundsson, Julius; Thorleifsson, Gudmar; Weinstock, Joshua; Zawistowski, Matthew; Nielsen, Jonas Bille; Chaker, Layal; Medici, Marco; Teumer, Alexander; Naitza, Silvia; Sanna, Serena; Schultheiss, Ulla T.; Cappola, Anne R.; Karjalainen, Juha; Kurki, Mitja I.; Oneka, Morgan; Taylor, Peter; Fritsche, Lars; Graham, Sarah E.; Wolford, Brooke N.; Overton, William; Rasheed, Humaira; Bordal, Eirin Haug; Gabrielsen, Maiken Elvestad; Skogholt, Anne Heidi; Surakka, Ida; Davey Smith, George; Pandit, Anita; Roychowdhury, Tanmoy; Hornsby, Whitney; Jonasson, Jon G.; Senter, Leigha; Liyanarachchi, Sandya; Ringel, Matthew D.; Xu, Li; Kiemeney, Lambertus A.; He, Huiling; Netea-Maier, Romana; Mayordomo, Jose; Plantinga, Theo S.; Hrafnkelsson, Jon; Hjartarson, Hannes; Sturgis, Erich M.; Palotie, Aarno; Daly, Mark J.; Citterio, Cintia E.; Arvan, Peter; Brummett, Chad M.; Boehnke, Michael; de la Chapelle, Albert; Stefansson, Kari; Hveem, Kristian; Willer, Cristen J.; Åsvold, Bjørn Olav
Peer reviewed, Journal article
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Date
2020Metadata
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- Institutt for samfunnsmedisin og sykepleie [3909]
- Publikasjoner fra CRIStin - NTNU [39915]
- St. Olavs hospital [2694]
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.