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

• Published in: The journal of clinical endocrinology and metabolism Vol. 106; no. 5; pp. e2191 - e2202
• Main Authors: Lafontaine, Nicole, Campbell, Purdey J, Castillo-Fernandez, Juan E, Mullin, Shelby, Lim, Ee Mun, Kendrew, Phillip, Lewer, Michelle, 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
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.05.2021
• Subjects: Adolescent; Analysis; Australia - epidemiology; Blood levels; Child; Clinical s; Cohort Studies; DNA methylation; Epigenetic inheritance; Epigenetics; Epigenome - physiology; Female; Genes; Genome-Wide Association Study; Genomes; Genomics; Histone-Lysine N-Methyltransferase - genetics; Humans; Kruppel-Like Transcription Factors - genetics; Male; Methylation; Observational Studies as Topic - statistics & numerical data; Pituitary; Thyroid Diseases - blood; Thyroid Diseases - epidemiology; Thyroid Diseases - genetics; Thyroid Function Tests; Thyroid gland; Thyroid Gland - physiology; Thyroid hormones; Thyroid-stimulating hormone; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine - blood; Twin Studies as Topic - statistics & numerical data; Australia; DNA methylation; EWAS; thyroid hormone; epigenetics; KLF9; DOT1L
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa975

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.