GWAS of Thyroid Stimulating Hormone Highlights Pleiotropic Effects and Inverse Association with Thyroid Cancer
Authors
Wei Zhou, University of Michigan, Ann Arbor
Ben Brumpton, Norwegian University of Science and Technology
Omer Kabil, University of Michigan, Ann Arbor
Julius Gudmundsson, deCODE genetics/AMGEN, Iceland
Gudmar Thorleifsson, deCODE genetics/AMGEN, Iceland
Josh Weinstock, University of Michigan, Ann Arbor
Matthew Zawistowski, University of Michigan, Ann Arbor
Jonas B. Nielsen, Norwegian University of Science and Technology
Layal Chaker, Erasmus MC Academic Center for Thyroid Diseases
Marco Medici, Erasmus MC Academic Center for Thyroid Diseases
Alexander Teumer, University Medicine Greifswald
Silvia Naitza, Istituto di Ricerca Genetica e Biomedica
Serena Sanna, Istituto di Ricerca Genetica e Biomedica
Ulla T. Schultheiss, University of Freiburg
Anne Cappola, University of Pennsylvania
Juha Karjalainen, Massachusetts General Hospital
Mitja Kurki, Massachusetts General Hospital
Morgan Oneka, University of Michigan, Ann Arbor
Peter Taylor, Cardiff University
Lars G. Fritsche, University of Michigan, Ann Arbor
Sarah E. Graham, University of Michigan, Ann Arbor
Brooke N. Wolford, University of Michigan, Ann Arbor
William Overton, University of Michigan, Ann Arbor
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, Ann Arbor
George Davey Smith, University of Bristol
Anita Pandit, University of Michigan, Ann Arbor
Tanmoy Roychowdhury, University of Michigan, Ann Arbor
Whitney E. Hornsby, University of Michigan, Ann Arbor
Jon G. Jonasson, Landspitali-University Hospital
Leigha Senter, Ohio State University
Sandya Liyanarachchi, Ohio State University
Matthew D. Ringel, Ohio State University
Li Xu, The University of Texas MD Anderson Cancer Center
Lambertus E. Kiemeney, Radboud Institute for Health Sciences
Huiling He, Ohio State University
Romana T. Netea-Maier, Radboud University
Jose I. Mayordomo, University of Colorado Hospital
Theo S. Plantinga, Radboud University
Jon Hrafnkelsson, Landspitali-University Hospital
Hannes Hjartarson, Landspitali-University Hospital
Erich M. Sturgis, The University of Texas MD Anderson Cancer Center
Aarno Palotie, Massachusetts General Hospital
Mark Daly, Massachusetts General Hospital
Cintia E. Citterio, Chapman UniversityFollow
Peter Arvan, University of Michigan, Ann Arbor
Chad M. Brummett, University of Michigan, Ann Arbor
Michael Boehnke, University of Michigan, Ann Arbor
Albert de la Chappelle, Ohio State University
Kari Stefansson, deCODE genetics/AMGEN, Iceland
Kristian Hveem, Norwegian University of Science and Technology
Christen J. Willer, University of Michigan, Ann Arbor
Bjørn Olav Åsvold, Norwegian University of Science and Technology
Publication Date
8-7-2020
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.
Recommended Citation
Zhou, W., Brumpton, B., Kabil, O. et al. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nat Commun 11, 3981 (2020). https://doi.org/10.1038/s41467-020-17718-z
Comments
This article was originally published in Nature Communications, volume 11, issue 1, in 2020. https://doi.org/10.1038/s41467-020-17718-z
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A correction was posted on December 16, 2021 and the PDF reflects the corrected information.