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| PMID |
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| TITLE |
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| Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L. |
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| ABSTRACT |
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| 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. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2020/08/14 |
| entrez |
2021/01/23 08:34 |
| pubmed |
2021/01/24 06:00 |
| medline |
2021/01/24 06:00 |
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| AUTHORS |
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| 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 |
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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. |
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| INVESTIGATORS |
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| JOURNAL |
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| 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 |
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| MEDLINE JOURNAL |
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| MEDLINETA: J Clin Endocrinol Metab |
| COUNTRY: United States |
| ISSNLINKING: 0021-972X |
| NLMUNIQUEID: 0375362 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GENERAL NOTE |
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| KEYWORDS |
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| KEYWORD |
| DNA methylation |
| DOT1L |
| EWAS |
| KLF9 |
| epigenetics |
| thyroid hormone |
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| MESH HEADINGS |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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