Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L
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Context: Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited. Objective: To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. Method: We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed. Results: We identified 2 DMPs with epigenome-wide significant (P < 2.4E−7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E−10) and cg04173586 in DOT1L (P = 2.09E−16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH. Conclusions: This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
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Systematic studies in healthy mono- and dizygotic twins, repetitive sampling studies, and testing of individuals or subpopulations in different regions have shown markedly narrower within-subject variability than between-subject variations.
“Results from systematic studies in healthy mono- and dizygotic twins, repetitive sampling studies, and the testing of individuals or (sub-)populations in different regions have shown markedly narrower within-subject variability (e.g., during monthly sampling) than between-subject variations.”
Population-based reference intervals for thyroid test variables are much broader than the narrow within-subject variance and consequently are less useful for monitoring an individual patient.
“Population-based reference intervals for thyroid test variables are, therefore, much broader than the rather narrow within-subject variance and consequently are less useful for monitoring an individual patient.108–113”
Heritability accounts for 30% to 65% of the variance in TSH, fT4, fT3, and the fT4 × TSH product.
“Such studies reveal that heritability accounts for 30% to 65% of the variance in TSH, fT4, fT3, and the fT4 × TSH product.”
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References 81 · Cited by 17
- Authors
- Lafontaine, N., Campbell, P. J., Castillo-Fernandez, J. E., Mullin, S., Lim, E. M., Kendrew, P., Lewer, M., Brown, S. J., Huang, R.-C., Melton, P. E., Mori, T. A., Beilin, L. J., Dudbridge, F., Spector, T. D., Wright, M. J., Martin, N. G., McRae, A. F., Panicker, V., Zhu, G., Walsh, J. P., Bell, J. T., & Wilson, S. G.
- Affiliations
- The University of Western Australia (AU)
- Sir Charles Gairdner Hospital (AU)
- Department of Twin Research & Genetic Epidemiology, King’s College London, London, UK
- Pathwest Laboratory Medicine (AU)
- The Kids Research Institute Australia (AU)
- University of Tasmania (AU)
- University of Leicester (GB)
- King's College London (GB)
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- Lafontaine, Nicole
- ORCID
- Lafontaine, Nicole
- Campbell, Purdey J
- Castillo-Fernandez, Juan E
- Mullin, Shelby
- Lim, Ee Mun
- Brown, Suzanne J
- Huang, Rae-Chi
- Melton, Phillip E
- Mori, Trevor A
- Beilin, Lawrence J
- Dudbridge, Frank
- Spector, Tim D
- Wright, Margaret J
- Martin, Nicholas G
- McRae, Allan F
- Panicker, Vijay
- Zhu, Gu
- Walsh, John P
- Bell, Jordana T
- Wilson, Scott G
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2021-01-23
- Volume
- 106
- Issue
- 5
- Pages
- e2191-e2202
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC8063248
- OpenAlex
- W3124332596
- Cited by
- 17
- References
- 81
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 8 · 2022: 2 · 2021: 3
- FWCI
- 0.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- UTAS Research Repository (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- NHMRC (1031119, 1010374, 496667, 1046880, 1087407)
- National Institutes of Health
- Australian Research Council (A7960034, A79906588, A79801419, DP0212016, DP0343921, DP1093900)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- free triiodothyronine, free thyroxine, thyroid-stimulating hormone, thyroid function, DNA methylation, differentially methylated positions, KLF9, DOT1L, pituitary-thyroid axis, thyroid hormone action, epigenome-wide association study, adolescents
- MeSH terms
- Epigenome, Adolescent, Australia, Child, Female, Humans, Male, Histone-Lysine N-Methyltransferase, Thyroid Diseases, Thyroid Function Tests, Thyroid Gland, Triiodothyronine, Cohort Studies, Twin Studies as Topic, Kruppel-Like Transcription Factors, Genome-Wide Association Study, Observational Studies as Topic
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