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

Wei Zhou(Broad Institute), Ben Brumpton(Norwegian University of Science and Technology), Ömer Kabil(University of Michigan), Jūlı́us Guðmundsson(deCODE Genetics (Iceland)), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Joshua S. Weinstock(University of Michigan), Matthew Zawistowski(University of Michigan), Jonas B. Nielsen(Statens Serum Institut), Layal Chaker(Erasmus MC), Marco Medici(Radboud University Nijmegen), Alexander Teumer(Universitätsmedizin Greifswald), Silvia Naitza(Institute of Genetic and Biomedical Research), Serena Sanna(University Medical Center Groningen), Ulla T. Schultheiß(University of Freiburg), Anne Rentoumis Cappola(University of Pennsylvania), Juha Karjalainen(Broad Institute), Mitja Kurki(Broad Institute), Morgan Oneka(University of Michigan), Peter Taylor(Cardiff University), Lars G. Fritsche(University of Michigan), Sarah E. Graham(University of Michigan), Brooke N. Wolford(University of Michigan), William Overton(University of Michigan), Humaira Rasheed(Norwegian University of Science and Technology), Eirin B. Haug(Norwegian University of Science and Technology), Maiken E. Gabrielsen(Norwegian University of Science and Technology), Anne Heidi Skogholt(Norwegian University of Science and Technology), Ida Surakka(University of Michigan), George Davey Smith(University of Bristol), Anita Pandit(University of Michigan), Tanmoy Roychowdhury(University of Michigan), Whitney Hornsby(University of Michigan), Jón G. Jónasson(Reykjavík University), Leigha Senter(The Ohio State University), Sandya Liyanarachchi, Matthew D. Ringel(The Ohio State University), Li Xu(The University of Texas MD Anderson Cancer Center), Lambertus A. Kiemeney(Radboud University Nijmegen), Huiling He, Romana T. Netea‐Maier(Radboud University Nijmegen), José Mayordomo(University of Colorado Hospital), Theo S. Plantinga(Radboud University Nijmegen), Jón Hrafnkelsson(Reykjavík University), Hannes Hjartarson(Reykjavík University), Erich M. Sturgis(The University of Texas MD Anderson Cancer Center), Aarno Palotie(Broad Institute), Mark J. Daly(Broad Institute), Cintia E. Citterio(Universidad de Buenos Aires), Peter Arvan(University of Michigan), Chad M. Brummett(University of Michigan), Michael Boehnke(University of Michigan), Albert de la Chapelle, Kāri Stefánsson(deCODE Genetics (Iceland)), Kristian Hveem(Norwegian University of Science and Technology), Cristen J. Willer(University of Michigan), Bjørn Olav Åsvold(Norwegian University of Science and Technology)
Nature Communications
August 7, 2020
10.1038/s41467-020-17718-z
Cited by 141Open Access
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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 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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