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

Author

Listed:
  • Wei Zhou

    (University of Michigan
    Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Broad Institute of Harvard and MIT)

  • Ben Brumpton

    (Norwegian University of Science and Technology
    University of Bristol
    St. Olavs Hospital, Trondheim University Hospital)

  • Omer Kabil

    (University of Michigan Medical School
    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
    University of Michigan Medical School
    Statens Serum Institute)

  • Layal Chaker

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center
    Erasmus Medical Center)

  • Marco Medici

    (Erasmus MC Academic Center for Thyroid Diseases
    Erasmus Medical Center
    Erasmus Medical Center
    Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences)

  • Alexander Teumer

    (University Medicine Greifswald
    Partner Site Greifswald)

  • Silvia Naitza

    (Consiglio Nazionale delle Ricerche Monserrato)

  • Serena Sanna

    (Consiglio Nazionale delle Ricerche Monserrato
    University of Groningen, University Medical Center Groningen)

  • Ulla T. Schultheiss

    (University of Freiburg
    University of Freiburg)

  • Anne Cappola

    (University of Pennsylvania School of Medicine)

  • Juha Karjalainen

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Broad Institute of Harvard and MIT
    University of Helsinki)

  • Mitja Kurki

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Broad Institute of Harvard and MIT
    University of Helsinki)

  • 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
    University of Michigan School of Public Health)

  • William Overton

    (University of Michigan School of Public Health)

  • Humaira Rasheed

    (Norwegian University of Science and Technology
    University of Bristol)

  • Eirin B. Haug

    (Norwegian University of Science and Technology
    University of Bristol)

  • Maiken E. Gabrielsen

    (Norwegian University of Science and Technology
    Norwegian University of Science and Technology, NTNU)

  • Anne Heidi Skogholt

    (Norwegian University of Science and Technology
    Norwegian University of Science and Technology, NTNU)

  • Ida Surakka

    (University of Michigan Medical School)

  • George Davey Smith

    (University of Bristol
    Bristol Medical School, 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
    University of Iceland
    The Icelandic Cancer Registry)

  • 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
    Broad Institute of Harvard and MIT
    Broad Institute of Harvard and MIT
    University of Helsinki)

  • Mark Daly

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Broad Institute of Harvard and MIT
    University of Helsinki)

  • Cintia E. Citterio

    (University of Michigan Medical School
    Inmunología y Biotecnología/Cátedra de Genética
    CONICET-Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM))

  • 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
    University of Iceland)

  • Kristian Hveem

    (Norwegian University of Science and Technology
    NTNU, Norwegian University of Science and Technology
    Nord-Trøndelag Hospital Trust)

  • Cristen J. Willer

    (University of Michigan
    University of Michigan Medical School
    University of Michigan)

  • Bjørn Olav Åsvold

    (Norwegian University of Science and Technology
    NTNU, Norwegian University of Science and Technology
    St. Olavs Hospital, Trondheim University Hospital)

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.

Suggested Citation

  • Wei Zhou & Ben Brumpton & Omer Kabil & Julius Gudmundsson & Gudmar Thorleifsson & Josh Weinstock & Matthew Zawistowski & Jonas B. Nielsen & Layal Chaker & Marco Medici & Alexander Teumer & Silvia Nait, 2020. "GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17718-z
    DOI: 10.1038/s41467-020-17718-z
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    Cited by:

    1. Rosalie B. T. M. Sterenborg & Inga Steinbrenner & Yong Li & Melissa N. Bujnis & Tatsuhiko Naito & Eirini Marouli & Tessel E. Galesloot & Oladapo Babajide & Laura Andreasen & Arne Astrup & Bjørn Olav Å, 2024. "Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Yuandan Wei & Jianxin Zhen & Liang Hu & Yuqin Gu & Yanhong Liu & Xinxin Guo & Zijing Yang & Hao Zheng & Shiyao Cheng & Fengxiang Wei & Likuan Xiong & Siyang Liu, 2024. "Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Alexander T. Williams & Jing Chen & Kayesha Coley & Chiara Batini & Abril Izquierdo & Richard Packer & Erik Abner & Stavroula Kanoni & David J. Shepherd & Robert C. Free & Edward J. Hollox & Nigel J. , 2023. "Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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