Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation
Open accessAbstract
Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
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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 [45]
The Discussion (page not available) calls this the largest GWAS of thyroid function and dysfunction and reports 109 independently associated variants. But the Introduction says that total covers TSH and FT4 levels as well as hypo- and hyperthyroidism; the Results figure specifies 61 TSH-associated and 31 FT4-associated GWAS SNPs. The source therefore supports the general-population GWAS framing, but not the claim that over 100 variants were associated with TSH or FT4 concentrations specifically. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCurrent polygenic risk scores focusing on thyroid function are too limited by their discriminatory power to be used in clinical practice.
“The current polygenic risk scores focusing on thyroid function 45,49 are too limited by their discriminatory power to be used in clinical practice.”
From Hypothyroidism (2024) · cites this paper as [45]
The Results section, “Genetic TSH and FT4 risk score associations” (page unavailable), reports that the FT4-based score was not significantly associated with hypo- or hyperthyroidism. But it also reports substantial differences in thyroid-dysfunction risk across TSH-based scores. The paper does not assess discriminatory power or conclude that these scores are too limited for clinical practice. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThis study identified 84 novel genetic variants and provided a rich resource for successful in-vitro studies.
“This study is currently the largest GWAS on autoimmune thyroid disease, and identified 84 novel genetic variants and provided a rich resource for successful in-vitro studies, unravelling the intricacies of thyroid hormone regulation and disease.45,50”
From Hypothyroidism (2024) · cites this paper as [45]
The Discussion (page unavailable) reports the largest GWAS of thyroid function and dysfunction, 109 independently associated variants, and functional characterization of a thyroid hormone transporter and metabolizing enzyme. The Results report 19 novel TSH loci and 16 novel FT4 loci, not 84 novel variants; the paper also does not describe its GWAS as specifically the largest on autoimmune thyroid disease. Its in-vitro work supports the claim's functional-studies aspect, but not the stated variant count or disease scope. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThyroid hormone levels are largely genetically determined, with similar genetic effects observed in children and adults.
“Furthermore, thyroid hormone levels are largely genetically determined [6–8] with similar genetic effects observed in children and adults [8].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [7]
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- Authors
- Teumer, A., Chaker, L., Groeneweg, S., Li, Y., Di Munno, C., Barbieri, C., Schultheiss, U. T., Traglia, M., Ahluwalia, T. S., Akiyama, M., Appel, E. V. R., Arking, D. E., Arnold, A., Astrup, A., Beekman, M., Beilby, J. P., Bekaert, S., Boerwinkle, E., Brown, S. J., De Buyzere, M., Campbell, P. J., Ceresini, G., Cerqueira, C., Cucca, F., Deary, I. J., Deelen, J., Eckardt, K.-U., Ekici, A. B., Eriksson, J. G., Ferrrucci, L., Fiers, T., Fiorillo, E., Ford, I., Fox, C. S., Fuchsberger, C., Galesloot, T. E., Gieger, C., Gögele, M., De Grandi, A., Grarup, N., Greiser, K. H., Haljas, K., Hansen, T., Harris, S. E., van Heemst, D., den Heijer, M., Hicks, A. A., den Hollander, W., Homuth, G., Hui, J., Ikram, M. A., Ittermann, T., Jensen, R. A., Jing, J., Jukema, J. W., Kajantie, E., Kamatani, Y., Kasbohm, E., Kaufman, J.-M., Kiemeney, L. A., Kloppenburg, M., Kronenberg, F., Kubo, M., Lahti, J., Lapauw, B., Li, S., Liewald, D. C. M., Study, L. C., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M. A., Wijmenga, C., Lim, E. M., Linneberg, A., Marina, M., Mascalzoni, D., Matsuda, K., Medenwald, D., Meisinger, C., Meulenbelt, I., De Meyer, T., Meyer zu Schwabedissen, H. E., Mikolajczyk, R., Moed, M., Netea-Maier, R. T., Nolte, I. M., Okada, Y., Pala, M., Pattaro, C., Pedersen, O., Petersmann, A., Porcu, E., Postmus, I., Pramstaller, P. P., Psaty, B. M., Ramos, Y. F. M., Rawal, R., Redmond, P., Richards, J. B., Rietzschel, E. R., Rivadeneira, F., Roef, G., Rotter, J. I., Sala, C. F., Schlessinger, D., Selvin, E., Slagboom, P. E., Soranzo, N., Sørensen, T. I. A., Spector, T. D., Starr, J. M., Stott, D. J., Taes, Y., Taliun, D., Tanaka, T., Thuesen, B., Tiller, D., Toniolo, D., Uitterlinden, A. G., Visser, W. E., Walsh, J. P., Wilson, S. G., Wolffenbuttel, B. H. R., Yang, Q., Zheng, H.-F., Cappola, A., Peeters, R. P., Naitza, S., Völzke, H., Sanna, S., Köttgen, A., Visser, T. J., & Medici, M.
- Affiliations
- Universitätsmedizin Greifswald (DE)
- Erasmus MC (NL)
- University of Freiburg (DE)
- IRCCS Ospedale San Raffaele (IT)
- University of Copenhagen (DK)
- RIKEN Center for Integrative Medical Sciences (JP)
- Johns Hopkins University (US)
- University of Washington (US)
- Leiden University Medical Center (NL)
- The University of Western Australia (AU)
- Ghent University Hospital (BE)
- The University of Texas Health Science Center at Houston (US)
- Sir Charles Gairdner Hospital (AU)
- University of Parma (IT)
- Frederiksberg Hospital (DK)
- University of Sassari (IT)
- University of Edinburgh (GB)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Helsinki (FI)
- National Institute on Aging (US)
- Institute of Genetic and Biomedical Research (IT)
- University of Glasgow (GB)
- Brigham and Women's Hospital (US)
- Eurac Research (IT)
- Radboud University Medical Center (NL)
- Helmholtz Munich (DE)
- German Cancer Research Center (DE)
- Institute of Genetics and Cancer (GB)
- Kyoto University (JP)
- Friedrich-Loeffler-Institut (DE)
- Innsbruck Medical University (AT)
- Boston University (US)
- University Medical Center Groningen (NL)
- Martin Luther University Halle-Wittenberg (DE)
- SIB Swiss Institute of Bioinformatics (CH)
- Kaiser Permanente Washington Health Research Institute (US)
- King's College London (GB)
- National Institutes of Health (US)
- Alzheimer Scotland (GB)
- AZ Sint-Jan (BE)
- Hangzhou Normal University (CN)
- Corresponding author
- Teumer, Alexander
- ORCID
- Teumer, Alexander
- Chaker, Layal
- Groeneweg, Stefan
- Li, Yong
- Barbieri, Caterina
- Schultheiss, Ulla T.
- Traglia, Michela
- Ahluwalia, Tarunveer S.
- Akiyama, Masato
- Appel, Emil Vincent R.
- Arking, Dan E.
- Arnold, Alice
- Astrup, Arne
- Beekman, Marian
- Beilby, John P.
- Bekaert, Sofie
- Boerwinkle, Eric
- Brown, Suzanne J.
- Campbell, Purdey J.
- Ceresini, Graziano
- Cucca, Francesco
- Deary, Ian J.
- Deelen, Joris
- Eckardt, Kai-Uwe
- Ekici, Arif B.
- Eriksson, Johan G.
- Fiers, Tom
- Fiorillo, Edoardo
- Ford, Ian
- Fox, Caroline S.
- Fuchsberger, Christian
- Galesloot, Tessel E.
- Gieger, Christian
- Gögele, Martin
- Grarup, Niels
- Greiser, Karin Halina
- Haljas, Kadri
- Hansen, Torben
- Harris, Sarah E.
- Hicks, Andrew A.
- Homuth, Georg
- Hui, Jennie
- Ikram, M. Arfan
- Ittermann, Till
- Jukema, J. Wouter
- Kajantie, Eero
- Kamatani, Yoichiro
- Kasbohm, Elisa
- Kaufman, Jean-Marc
- Kiemeney, Lambertus A.
- Kloppenburg, Margreet
- Kronenberg, Florian
- Kubo, Michiaki
- Lahti, Jari
- Lapauw, Bruno
- Li, Shuo
- Liewald, David C. M.
- Alizadeh, Behrooz Z.
- Boezen, H. Marike
- Franke, Lude
- Navis, Gerjan
- Snieder, Harold
- Swertz, Morris A.
- Wijmenga, Cisca
- Lim, Ee Mun
- Linneberg, Allan
- Mascalzoni, Deborah
- Matsuda, Koichi
- Medenwald, Daniel
- Meisinger, Christa
- Meulenbelt, Ingrid
- Mikolajczyk, Rafael
- Netea-Maier, Romana T.
- Nolte, Ilja M.
- Okada, Yukinori
- Pala, Mauro
- Pattaro, Cristian
- Pedersen, Oluf
- Porcu, Eleonora
- Pramstaller, Peter P.
- Psaty, Bruce M.
- Ramos, Yolande F. M.
- Rawal, Rajesh
- Redmond, Paul
- Richards, J. Brent
- Rietzschel, Ernst R.
- Rivadeneira, Fernando
- Rotter, Jerome I.
- Sala, Cinzia F.
- Schlessinger, David
- Selvin, Elizabeth
- Slagboom, P. Eline
- Soranzo, Nicole
- Sørensen, Thorkild I. A.
- Starr, John M.
- Stott, David J.
- Taliun, Daniel
- Tanaka, Toshiko
- Thuesen, Betina
- Toniolo, Daniela
- Visser, W. Edward
- Walsh, John P.
- Wilson, Scott G.
- Wolffenbuttel, Bruce H. R.
- Yang, Qiong
- Zheng, Hou-Feng
- Cappola, Anne
- Peeters, Robin P.
- Naitza, Silvia
- Völzke, Henry
- Sanna, Serena
- Köttgen, Anna
- Medici, Marco
- Venue
- Nature Communications
- Published
- 2018-10-26
- Volume
- 9
- Issue
- 1
- Pages
- 4455-4455
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6203810
- OpenAlex
- W2896468934
- Cited by
- 280
- References
- 64
- Citations by year
- 2026: 13 · 2025: 35 · 2024: 64 · 2023: 51 · 2022: 40 · 2021: 35 · 2020: 28 · 2019: 11 · 2018: 1
- FWCI
- 15.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Leiden Repository (Leiden University) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- IRIS (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- OpenAgrar (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion, cc-by)
- OPUS (Augsburg University) (submittedVersion, cc-by)
- Open Research (University of Surrey) (submittedVersion, other-oa)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- The list of funders and grants is provided in the Supplementary Note 4 of the Supplementary Information.
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- thyroid hormone regulation, thyroid dysfunction, Graves' disease, subclinical thyroid dysfunction, thyroid hormone transport, thyroid hormone metabolism, polygenic risk score, genetic variants
- MeSH terms
- Animals, Biological Transport, Chlorocebus aethiops, Gene Expression Regulation, Humans, Hyperthyroidism, Hypothyroidism, Risk Factors, Thyroid Gland, Thyroid Hormones, Thyrotropin, COS Cells, Polymorphism, Single Nucleotide, White People, Sodium-Phosphate Cotransporter Proteins, Type I, 2-Aminoadipate Transaminase, Genome-Wide Association Study
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