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Meta-Analysis
. 2021 Apr 23;106(5):e2191-e2202.
doi: 10.1210/clinem/dgaa975.

Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L

Nicole Lafontaine  1   2 , Purdey J Campbell  1 , Juan E Castillo-Fernandez  3 , Shelby Mullin  1 , Ee Mun Lim  1   4 , Phillip Kendrew  4 , Michelle Lewer  4 , Suzanne J Brown  1 , Rae-Chi Huang  5 , Phillip E Melton  6   7   8 , Trevor A Mori  9 , Lawrence J Beilin  9 , Frank Dudbridge  10 , Tim D Spector  3 , Margaret J Wright  11   12 , Nicholas G Martin  13 , Allan F McRae  14 , Vijay Panicker  1 , Gu Zhu  13 , John P Walsh  1   2 , Jordana T Bell  3 , Scott G Wilson  1   3   6
Affiliations
Meta-Analysis

Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L

Nicole Lafontaine et al. J Clin Endocrinol Metab. .

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.

Keywords: DNA methylation; DOT1L; EWAS; KLF9; epigenetics; thyroid hormone.

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Figures

Figure 1.
Figure 1.
Miami plot of meta-analysis of EWAS for fT3 (top panel) and for TSH (bottom panel). The x-axis shows chromosome position, and the y-axis the −log10P values. The epigenome-wide significance threshold is represented by the horizontal red lines (P = 2.4E−7) and the threshold for suggestive association shown by the blue horizontal lines (P = 1.0E−5).
Figure 2.
Figure 2.
Local association plots describing the genomic region for each of the significant DMP (top panel), the functional annotation (middle panel), and the pattern of co-methylation at individual CpG sites at 2a, cg00049440 and 2b, cg04713586. Co-methylation relationships are derived from BSGS participants.
Figure 2.
Figure 2.
Local association plots describing the genomic region for each of the significant DMP (top panel), the functional annotation (middle panel), and the pattern of co-methylation at individual CpG sites at 2a, cg00049440 and 2b, cg04713586. Co-methylation relationships are derived from BSGS participants.
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