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

Public Time: 2020-08-07 00:00:00
Journal: Nature Communications
doi: 10.1038/s41467-020-17718-z
Author: Wei Zhou;Ben 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 T. Schultheiss;Anne Cappola;Juha Karjalainen;Mitja Kurki;Morgan Oneka;Peter Taylor;Lars G. Fritsche;Sarah E. Graham;Brooke N. Wolford;William Overton;Humaira Rasheed;Eirin B. Haug;Maiken E. Gabrielsen;Anne Heidi Skogholt;Ida Surakka;George Davey Smith;Anita Pandit;Tanmoy Roychowdhury;Whitney E. Hornsby;Jon G. Jonasson;Leigha Senter;Sandya Liyanarachchi;Matthew D. Ringel;Li Xu;Lambertus A. Kiemeney;Huiling He;Romana T. Netea-Maier;Jose I. Mayordomo;Theo S. Plantinga;Jon Hrafnkelsson;Hannes Hjartarson;Erich M. Sturgis;Aarno Palotie;Mark Daly;Cintia E. Citterio;Peter Arvan;Chad M. Brummett;Michael Boehnke;Albert de la Chapelle;Kari Stefansson;Kristian Hveem;Cristen J. Willer;Bjørn Olav Åsvold
Summary: 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.
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