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

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 Chapelle, Kari Stefansson, Kristian Hveem, Cristen J. Willer and Bjørn Olav Åsvold ()
Additional contact information
Wei Zhou: University of Michigan
Ben Brumpton: Norwegian University of Science and Technology
Omer Kabil: University of Michigan Medical School
Julius Gudmundsson: deCODE genetics/AMGEN
Gudmar Thorleifsson: deCODE genetics/AMGEN
Josh Weinstock: University of Michigan School of Public Health
Matthew Zawistowski: University of Michigan School of Public Health
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: Consiglio Nazionale delle Ricerche Monserrato
Serena Sanna: Consiglio Nazionale delle Ricerche Monserrato
Ulla T. Schultheiss: University of Freiburg
Anne Cappola: University of Pennsylvania School of Medicine
Juha Karjalainen: Massachusetts General Hospital
Mitja Kurki: Massachusetts General Hospital
Morgan Oneka: University of Michigan
Peter Taylor: Cardiff University School of Medicine
Lars G. Fritsche: University of Michigan School of Public Health
Sarah E. Graham: University of Michigan Medical School
Brooke N. Wolford: University of Michigan
William Overton: University of Michigan School of Public Health
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 Medical School
George Davey Smith: University of Bristol
Anita Pandit: University of Michigan School of Public Health
Tanmoy Roychowdhury: University of Michigan Medical School
Whitney E. Hornsby: University of Michigan Medical School
Jon G. Jonasson: Landspitali-University Hospital
Leigha Senter: Ohio State University Comprehensive Cancer Center
Sandya Liyanarachchi: Ohio State University Comprehensive Cancer Center
Matthew D. Ringel: The Ohio State University
Li Xu: The University of Texas MD Anderson Cancer Center
Lambertus A. Kiemeney: Radboud Institute for Health Sciences
Huiling He: Ohio State University Comprehensive Cancer Center
Romana T. Netea-Maier: Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
Jose I. Mayordomo: University of Colorado Hospital
Theo S. Plantinga: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences
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: University of Michigan Medical School
Peter Arvan: University of Michigan Medical School
Chad M. Brummett: University of Michigan Medical School
Michael Boehnke: University of Michigan School of Public Health
Albert Chapelle: Ohio State University Comprehensive Cancer Center
Kari Stefansson: deCODE genetics/AMGEN
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, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17718-z

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