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Epigenome-wide association study of thyroid function traits identifies novel associations of fT3 with KLF9 and DOT1L
Lafontaine, M and Campbell, PJ and Castillo-Fernandez, JE and Mullin, S and Lim, EM and Kendrew, P and Lewer, M and Brown, SJ and Huang, R-C and Melton, PE and Mori, TA and Beilin, LJ and Dudbridge, F and Spector, TD and Wright, MJ and Martin, NG and McRae, AF and Panicker, V and Zhu, G and Walsh, JP and Bell, JT and Wilson, SG, Epigenome-wide association study of thyroid function traits identifies novel associations of fT3 with KLF9 and DOT1L, Journal of Clinical Endocrinology and Metabolism, 106, (5) pp. e2191-e2202. ISSN 0021-972X (2021) [Refereed Article]
Copyright 2021 The authors. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.
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.
|Item Type:||Refereed Article|
|Keywords:||DNA methylation, DOT1L, EWAS, KLF9, epigenetics, thyroid hormone|
|Research Division:||Biological Sciences|
|Research Field:||Epigenetics (incl. genome methylation and epigenomics)|
|Objective Group:||Evaluation of health and support services|
|Objective Field:||Determinants of health|
|UTAS Author:||Melton, PE (Dr Phillip Melton)|
|Web of Science® Times Cited:||5|
|Deposited By:||Menzies Institute for Medical Research|
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