GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
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Published:2020-08-07
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhou WeiORCID, Brumpton BenORCID, Kabil Omer, Gudmundsson Julius, Thorleifsson Gudmar, Weinstock JoshORCID, Zawistowski MatthewORCID, Nielsen Jonas B.ORCID, Chaker Layal, Medici Marco, Teumer AlexanderORCID, Naitza Silvia, Sanna SerenaORCID, Schultheiss Ulla T., Cappola Anne, Karjalainen Juha, Kurki Mitja, Oneka MorganORCID, Taylor Peter, Fritsche Lars G.ORCID, Graham Sarah E.ORCID, Wolford Brooke N.ORCID, Overton William, Rasheed HumairaORCID, Haug Eirin B., Gabrielsen Maiken E., Skogholt Anne Heidi, Surakka Ida, Davey Smith GeorgeORCID, Pandit Anita, Roychowdhury Tanmoy, Hornsby Whitney E., Jonasson Jon G., Senter Leigha, Liyanarachchi Sandya, Ringel Matthew D., Xu Li, Kiemeney Lambertus A.ORCID, He Huiling, Netea-Maier Romana T.ORCID, Mayordomo Jose I., Plantinga Theo S.ORCID, Hrafnkelsson Jon, Hjartarson Hannes, Sturgis Erich M., Palotie Aarno, Daly Mark, Citterio Cintia E.ORCID, Arvan Peter, Brummett Chad M., Boehnke MichaelORCID, de la Chapelle AlbertORCID, Stefansson KariORCID, Hveem Kristian, Willer Cristen J.ORCID, Åsvold Bjørn OlavORCID
Abstract
AbstractThyroid 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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