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

Document Type

Article

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.

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.

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

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.