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
- Fritsche, Lars G.
- Graham, Sarah E.
- Wolford, Brooke N.
- Overton, William
- Rasheed, Humaira
- Haug, Eirin B.
- Gabrielsen, Maiken E.
- Skogholt, Anne Heidi
- Surakka, Ida
- Smith, George Davey
- Pandit, Anita
- Roychowdhury, Tanmoy
- Hornsby, Whitney E.
- Jonasson, Jon G.
- Senter, Leigha
- Liyanarachchi, Sandya
- Ringel, Matthew D.
- Xu, Li
- Kiemeney, Lambertus E.
- 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 Chappelle, Albert
- Stefansson, Kari
- Hveem, Kristian
- Willer, Christen J.
- Åsvold, Bjørn Olav
DOIAbstract
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 random...
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