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Cited by 132Genetic Associations and EpidemiologyThyroid Disorders and TreatmentsThyroid Cancer Diagnosis and Treatment

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

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Zhou, Wei, Brumpton, Ben, Kabil, Omer, Gudmundsson, Julius, Thorleifsson, Gudmar, Weinstock, Josh, Zawistowski, Matthew, Nielsen, Jonas B., Chaker, Layal, Medici, Marco, Teumer, Alexander, Naitza, Silvia, Sanna, Serena, Schultheiss, Ulla T., Cappola, Anne, Karjalainen, Juha, Kurki, Mitja, Oneka, Morgan, Taylor, Peter, Fritsche, Lars G., Graham, Sarah E., Wolford, Brooke N., Overton, William, Rasheed, Humaira, Haug, Eirin B., Gabrielsen, Maiken E., Skogholt, Anne Heidi, Surakka, Ida, Davey Smith, George, Pandit, Anita, Roychowdhury, Tanmoy, Hornsby, Whitney E., Jonasson, Jon G., Senter, Leigha, Liyanarachchi, Sandya, Ringel, Matthew D., Xu, Li, Kiemeney, Lambertus A., He, Huiling, Netea-Maier, Romana T., Mayordomo, Jose I., Plantinga, Theo S., Hrafnkelsson, Jon, Hjartarson, Hannes, Sturgis, Erich M., Palotie, Aarno, Daly, Mark, Citterio, Cintia E., Arvan, Peter, Brummett, Chad M., Boehnke, Michael, de la Chapelle, Albert, Stefansson, Kari, Hveem, Kristian, Willer, Cristen J., Åsvold, Bjørn Olav·2020·Nature Communications
DOI 10.1038/s41467-020-17718-zPMC PMC7414135
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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.

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Fig. 1 Both the TG-P118L and TG-G67S point mutants exhibit a secretion defect. a–c Three independent replicate experiments. Western blotting of TG in 293T cells that were either untransfected (a, no detectable bands) or transfected with constructs encoding mouse TG wild type (WT) or P118L or G67S point mutants (in the pcDNA3.1 background, in which the CMV promoter drives the respective cDNA expression). Serum-free media (M) were collected overnight and the cells (C) were lysed. Equal volumes of media and cells were analyzed by SDS-PAGE, electrotransfer to nitrocellulose, and immunoblotting with anti-Tg-specific antibodies. Full scans of western blotting are presented in Supplementary Fig. 14. From scanning densitometry, d shows the content of thyroglobulin (and its variants) intracellularly and in the secretion. e The extracellular : intracellular (M/C) ratio of each construct. d, e Three independent replicate experiments. All boxplots in d and e indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers).
Fig. 1 Both the TG-P118L and TG-G67S point mutants exhibit a secretion defect. a–c Three independent replicate experiments. Western blotting of TG in 293T cells that were either untransfected (a, no detectable bands) or transfected with constructs encoding mouse TG wild type (WT) or P118L or G67S point mutants (in the pcDNA3.1 background, in which the CMV promoter drives the respective cDNA expression). Serum-free media (M) were collected overnight and the cells (C) were lysed. Equal volumes of media and cells were analyzed by SDS-PAGE, electrotransfer to nitrocellulose, and immunoblotting with anti-Tg-specific antibodies. Full scans of western blotting are presented in Supplementary Fig. 14. From scanning densitometry, d shows the content of thyroglobulin (and its variants) intracellularly and in the secretion. e The extracellular : intracellular (M/C) ratio of each construct. d, e Three independent replicate experiments. All boxplots in d and e indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers).CC BY · PubMed Central
Fig. 2 The risk of thyroid cancer is lower for individuals with genetically predicted higher TSH levels. Plots of thyroid cancer prevalence by quintiles of TSH PGS (left) and odds ratio of thyroid cancer in relation to the lowest quintile (right) in data sets UKBB (a; N case = 358, N control = 407,399), deCODE (b; N case = 1003, N control = 278,991)19, and FinnGen (c; N case = 501, N control = 135,137). N: sample size. N case: sample size of cases. N control: sample size of controls. Error bars represent 95% confidence intervals.
Fig. 2 The risk of thyroid cancer is lower for individuals with genetically predicted higher TSH levels. Plots of thyroid cancer prevalence by quintiles of TSH PGS (left) and odds ratio of thyroid cancer in relation to the lowest quintile (right) in data sets UKBB (a; N case = 358, N control = 407,399), deCODE (b; N case = 1003, N control = 278,991)19, and FinnGen (c; N case = 501, N control = 135,137). N: sample size. N case: sample size of cases. N control: sample size of controls. Error bars represent 95% confidence intervals.CC BY · PubMed Central
Fig. 3 Two-sample Mendelian randomization analysis for casual associations between TSH and thyroid cancer and between TSH and goiter. a. Two-sample MR between TSH and thyroid cancer based on summary statistics from the meta-analysis of HUNT and ThyroidOmics (n = 106,360) for TSH and from the meta-analysis of UKBB27,28, MGI26, deCODE and four other case–control data sets with European ancestry as reported in Gudmundsson et al.19 for thyroid cancer association (cases/controls = 4,146/731,903). b TSH and goiter based on summary statistics from the same TSH meta-analysis as above and from the GWAS of UKBB27,28 for goiter association (N case = 1,143, N control = 391,429) The crosshairs on the plots represent the 95% confidence intervals for each SNP-TSH or SNP-outcome association. The variant on the top left corner is the rare nonsynonymous variant B4GALNT3 p.R724W (rs145153320). N: sample size. N case: sample size of cases. N control: sample size of controls.
Fig. 3 Two-sample Mendelian randomization analysis for casual associations between TSH and thyroid cancer and between TSH and goiter. a. Two-sample MR between TSH and thyroid cancer based on summary statistics from the meta-analysis of HUNT and ThyroidOmics (n = 106,360) for TSH and from the meta-analysis of UKBB27,28, MGI26, deCODE and four other case–control data sets with European ancestry as reported in Gudmundsson et al.19 for thyroid cancer association (cases/controls = 4,146/731,903). b TSH and goiter based on summary statistics from the same TSH meta-analysis as above and from the GWAS of UKBB27,28 for goiter association (N case = 1,143, N control = 391,429) The crosshairs on the plots represent the 95% confidence intervals for each SNP-TSH or SNP-outcome association. The variant on the top left corner is the rare nonsynonymous variant B4GALNT3 p.R724W (rs145153320). N: sample size. N case: sample size of cases. N control: sample size of controls.CC BY · PubMed Central

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  1. National Academies Press. Medicare Coverage of Routine Screening for Thyroid Dysfunction (National Academies Press, USA, 2003).

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Authors
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., 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.
Affiliations
  • Broad Institute (US)
  • Norwegian University of Science and Technology (NO)
  • University of Michigan (US)
  • Statens Serum Institut (DK)
  • Erasmus MC (NL)
  • Universitätsmedizin Greifswald (DE)
  • Institute of Genetic and Biomedical Research (IT)
  • University Medical Center Groningen (NL)
  • University of Freiburg (DE)
  • University of Pennsylvania (US)
  • Cardiff University (GB)
  • University of Iceland (IS)
  • The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
  • The Ohio State University (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Radboud University Medical Center (NL)
  • University of Colorado Hospital (US)
  • Radboud University Nijmegen (NL)
  • National University Hospital of Iceland (IS)
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
Corresponding author
  • Zhou, Wei
  • Åsvold, Bjørn Olav
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-08-07
Volume
11
Issue
1
Pages
3981-3981
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-17718-z
PMC
PMC7414135
OpenAlex
W3042855021
Cited by
129
References
65
Citations by year
2026: 9 · 2025: 17 · 2024: 26 · 2023: 29 · 2022: 29 · 2021: 16 · 2020: 3
FWCI
11.29
Type
journal article
Language
en
Update notices
correction (2021-12-16)
Open access
Licence
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  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
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  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • Explore Bristol Research (acceptedVersion, cc-by)
  • Opin vísindi (Opin vísindi) (acceptedVersion, other-oa)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Chapman University Digital Commons (Chapman University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • CONICET Digital (CONICET) (submittedVersion, cc-by)
  • Hirsla (Landspítali University Hospital) (submittedVersion, other-oa)
Funders
  • Ohio State University
  • University of Michigan
  • Norges Teknisk-Naturvitenskapelige Universitet
  • University of Bristol (MC_UU_00011/1)
  • Helse Midt-Norge
  • Norges Forskningsråd
  • National Institutes of Health (24460, NIH-R01, DK062370)
  • Fakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige Universitet
  • Medical Research Council (MC_PC_17228, MC_UU_00011/1, MC_UU_00011)
  • Faculty of Medicine and Health, University of Sydney
  • Norwegian Institute of Public Health
  • National Institute on Aging (K24AG042765)
  • National Heart, Lung, and Blood Institute (R35HL135824, R01HL105756, R01HL109946)
  • National Human Genome Research Institute (T32HG000040, T32HG010464)
  • National Cancer Institute (P50CA168505, P30CA016058)
  • National Institute of General Medical Sciences (T32GM070449)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK062370, R56DK062370, R01DK040344, P30DK020572, R01DK062370)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
thyroid-stimulating hormone, TSH levels, thyroid cancer, goiter, pleiotropy, thyroglobulin, thyroglobulin secretion, genetic loci, polygenic risk score, Mendelian randomization, thyroid function, thyroid tumors, phenome-wide association study
MeSH terms
Goiter, Humans, Phenotype, Risk Factors, Thyroglobulin, Thyroid Neoplasms, Thyrotropin, Prevalence, Genetic Predisposition to Disease, Mutation, Missense, Physical Chromosome Mapping, Multifactorial Inheritance, Genome-Wide Association Study, Genetic Loci, Mendelian Randomization Analysis, Genetic Pleiotropy

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