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PMID
33484127
TITLE
Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L.
ABSTRACT
CONTEXT NlmCategory: BACKGROUND
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 NlmCategory: OBJECTIVE
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. To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.
METHOD NlmCategory: METHODS
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. To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. 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 NlmCategory: RESULTS
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. To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. 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. 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 NlmCategory: CONCLUSIONS
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. To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. 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. 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. 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.
The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
DATE PUBLISHED
2021 Jan 23
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2020/08/14
entrez 2021/01/23 08:34
pubmed 2021/01/24 06:00
medline 2021/01/24 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Lafontaine N Lafontaine Nicole N Medical School, University of Western Australia, Crawley, WA, Australia.
Campbell PJ Campbell Purdey J PJ Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Castillo-Fernandez JE Castillo-Fernandez Juan E JE Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Mullin S Mullin Shelby S Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Lim EM Lim Ee Mun EM Pathwest Laboratory Medicine, Nedlands, WA, Australia.
Kendrew P Kendrew Phillip P Pathwest Laboratory Medicine, Nedlands, WA, Australia.
Lewer M Lewer Michelle M Pathwest Laboratory Medicine, Nedlands, WA, Australia.
Brown SJ Brown Suzanne J SJ Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Huang RC Huang Rai-Chi RC Telethon Kids Institute, University of Western Australia, Perth, Australia.
Melton PE Melton Phillip E PE Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Mori TA Mori Trevor A TA Medical School, Royal Perth Hospital Unit, University of Western Australia, Perth, WA, Australia.
Beilin LJ Beilin Lawrence J LJ Medical School, Royal Perth Hospital Unit, University of Western Australia, Perth, WA, Australia.
Dudbridge F Dudbridge Frank F Department of Health Sciences, University of Leicester, Leicester, UK.
Spector TD Spector Tim D TD Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Wright MJ Wright Margaret J MJ Centre for Advanced Imaging, University of Queensland, Brisbane, Australia.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Australia.
McRae AF McRae Allan F AF Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Panicker V Panicker Vijay V Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Zhu G Zhu Gu G QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Walsh JP Walsh John P JP Medical School, University of Western Australia, Crawley, WA, Australia.
Bell JT Bell Jordana T JT Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Wilson SG Wilson Scott G SG School of Biomedical Sciences, University of Western Australia, Perth, Australia.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: The Journal of clinical endocrinology and metabolism
ISOABBREVIATION: J Clin Endocrinol Metab
YEAR: 2021
MONTH: Jan
DAY: 23
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1945-7197
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: J Clin Endocrinol Metab
COUNTRY: United States
ISSNLINKING: 0021-972X
NLMUNIQUEID: 0375362
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
DNA methylation
DOT1L
EWAS
KLF9
epigenetics
thyroid hormone
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's