GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
Open accessAbstract
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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The largest thyroid GWASs have identified over 100 genetic variants associated with TSH or FT4 concentrations, or both.
“The largest thyroid GWASs have focused on variations in thyroid hormone concentrations in the general population, identifying over 100 genetic variants associated with TSH or FT4 concentrations, or both.[45][46][47]”
From Hypothyroidism (2024) · cites this paper as [46]
The Results section (“Discovery of genetic loci for TSH”) reports a GWAS meta-analysis that identified 99 independent TSH-associated variants at 74 loci. That supports the general point that a large GWAS identified variants associated with thyroid-hormone regulation, but this paper does not establish the sentence’s threshold of over 100 variants; its GWAS focused on TSH rather than FT4. (LLM, conf=0.88)
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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
- Zhou, Wei
- Brumpton, Ben
- 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.
- 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.
- 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
- Venue
- Nature Communications
- Published
- 2020-08-07
- Volume
- 11
- Issue
- 1
- Pages
- 3981-3981
- ISSN
- 2041-1723 (ISSN-L)
- 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
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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