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. FritscheSarah 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 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 de la Chapelle, Kari Stefansson, Kristian Hveem, Cristen J. Willer, Bjorn Olav Asvold

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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.

Original languageEnglish
Article number3981
Number of pages13
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 7-Aug-2020

Keywords

  • ENDOGENOUS SUBCLINICAL HYPERTHYROIDISM
  • SERUM THYROTROPIN CONCENTRATION
  • GENOME-WIDE ASSOCIATION
  • CONGENITAL HYPOTHYROIDISM
  • COMMON VARIANTS
  • TSH
  • RECEPTOR
  • THYROGLOBULIN
  • HYPERTENSION
  • MALIGNANCY

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  • Author Correction: GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer

    Zhou, W., Brumpton, B., Kabil, O., Gudmundsson, J., Thorleifsson, G., Weinstock, J., Zawistowski, M., Nielsen, J. B., Chaker, L., Medici, M., Teumer, A., Naitza, S., Sanna, S., Schultheiss, U. T., Cappola, A., Karjalainen, J., Kurki, M., Oneka, M., Taylor, P. & Fritsche, L. G. & 36 others, Graham, S. E., Wolford, B. N., Overton, W., Rasheed, H., Haug, E. B., Gabrielsen, M. E., Skogholt, A. H., Surakka, I., Davey Smith, G., Pandit, A., Roychowdhury, T., Hornsby, W. E., Jonasson, J. G., Senter, L., Liyanarachchi, S., Ringel, M. D., Xu, L., Kiemeney, L. A., He, H., Netea-Maier, R. T., Mayordomo, J. I., Plantinga, T. S., Hrafnkelsson, J., Hjartarson, H., Sturgis, E. M., Palotie, A., Daly, M., Citterio, C. E., Arvan, P., Brummett, C. M., Boehnke, M., de la Chapelle, A., Stefansson, K., Hveem, K., Willer, C. J. & Åsvold, B. O., 16-Dec-2021, In: Nature Communications. 12, 1, p. 7354 7354.

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