Nicole Lafontaine1,2, Purdey J Campbell1, Juan E Castillo-Fernandez3, Shelby Mullin1, Ee Mun Lim1,4, Phillip Kendrew4, Michelle Lewer4, Suzanne J Brown1, Rae-Chi Huang5, Phillip E Melton6,7,8, Trevor A Mori9, Lawrence J Beilin9, Frank Dudbridge10, Tim D Spector3, Margaret J Wright11,12, Nicholas G Martin13, Allan F McRae14, Vijay Panicker1, Gu Zhu13, John P Walsh1,2, Jordana T Bell3, Scott G Wilson1,3,6. 1. Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. 2. Medical School, University of Western Australia, Crawley, WA, Australia. 3. Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. 4. Pathwest Laboratory Medicine, Nedlands, WA, Australia. 5. Telethon Kids Institute, University of Western Australia, Perth, Australia. 6. School of Biomedical Sciences, University of Western Australia, Perth, Australia. 7. School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia. 8. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. 9. Medical School, Royal Perth Hospital Unit, University of Western Australia, Perth, WA, Australia. 10. Department of Health Sciences, University of Leicester, Leicester, UK. 11. Queensland Brain Institute, University of Queensland, Brisbane, Australia. 12. Centre for Advanced Imaging, University of Queensland, Brisbane, Australia. 13. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 14. Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Abstract
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.
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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