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| ABSTRACT |
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| Thyroid hormones play a key role in differentiation and metabolism and are known regulators of gene expression through both genomic and epigenetic processes including DNA methylation. The aim of this study was to examine associations between thyroid hormones and DNA methylation. We carried out a fixed-effect meta-analysis of epigenome-wide association study (EWAS) of blood DNA methylation sites from 8 cohorts from the ThyroidOmics Consortium, incorporating up to 7073 participants of both European and African ancestry, implementing a discovery and replication stage. Statistical analyses were conducted using normalized beta CpG values as dependent and log-transformed thyrotropin (TSH), free thyroxine, and free triiodothyronine levels, respectively, as independent variable in a linear model. The replicated findings were correlated with gene expression levels in whole blood and tested for causal influence of TSH and free thyroxine by two-sample Mendelian randomization (MR). Epigenome-wide significant associations ( -value <1.1E-7) of three CpGs for free thyroxine, five for free triiodothyronine, and two for TSH concentrations were discovered and replicated (combined -values = 1.5E-9 to 4.3E-28). The associations included CpG sites annotated to (cg00049440) and (cg04173586) that overlap with all three traits, consistent with hypothalamic-pituitary-thyroid axis physiology. Significant associations were also found for CpGs in for free thyroxine, and at and for free triiodothyronine. MR analyses supported a causal effect of thyroid status on DNA methylation of . DNA methylation of cg00049440 in was inversely correlated with gene expression in blood. The CpG at overlapped with thyroid hormone receptor alpha binding peaks in liver cells. The total additive heritability of the methylation levels of the six significant CpG sites was between 25% and 57%. Significant methylation QTLs were identified for CpGs at , , , and . We report novel associations between TSH, thyroid hormones, and blood-based DNA methylation. This study advances our understanding of thyroid hormone action particularly related to and serves as a proof-of-concept that integrations of EWAS with other -omics data can provide a valuable tool for unraveling thyroid hormone signaling in humans by complementing and feeding classical and animal studies. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| pubmed |
2023/02/01 06:00 |
| medline |
2023/02/01 06:00 |
| entrez |
2023/01/31 12:12 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Weihs A |
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Weihs |
Antoine |
A |
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Department of Psychiatry and Psychotherapy; University Medicine Greifswald, Greifswald, Germany. |
| Chaker L |
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Chaker |
Layal |
L |
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Erasmus MC Academic Center for Thyroid Diseases, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Martin TC |
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Martin |
Tiphaine C |
TC |
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Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, King's College London, London, United Kingdom. |
| Braun KVE |
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Braun |
Kim V E |
KVE |
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Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Campbell PJ |
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Campbell |
Purdey J |
PJ |
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Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia. |
| Cox SR |
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Cox |
Simon R |
SR |
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Lothian Birth Cohorts, Department of Psychology; Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom. |
| Fornage M |
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Fornage |
Myriam |
M |
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Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. |
| Gieger C |
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Gieger |
Christian |
C |
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German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. |
| Grabe HJ |
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Grabe |
Hans J |
HJ |
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German Centre for Neurodegenerative Diseases (DZNE), Site Rostock, Greifswald, Germany. |
| Grallert H |
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Grallert |
Harald |
H |
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Institute of Epidemiology, Computational Health Center; Helmholtz Munich, Neuherberg, Germany. |
| Harris SE |
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Harris |
Sarah E |
SE |
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Lothian Birth Cohorts, Department of Psychology; Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom. |
| Kühnel B |
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Kühnel |
Brigitte |
B |
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Institute of Epidemiology, Computational Health Center; Helmholtz Munich, Neuherberg, Germany. |
| Marioni RE |
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Marioni |
Riccardo E |
RE |
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Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom. |
| Martin NG |
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Martin |
Nicholas G |
NG |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| McCartney DL |
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McCartney |
Daniel L |
DL |
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Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom. |
| McRae AF |
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McRae |
Allan F |
AF |
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Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia. |
| Meisinger C |
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Meisinger |
Christa |
C |
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Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany. |
| van Meurs JBJ |
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van Meurs |
Joyce B J |
JBJ |
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Department of Orthopeadics and Sports Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Nano J |
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Nano |
Jana |
J |
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Institute for Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany. |
| Nauck M |
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Nauck |
Matthias |
M |
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DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany. |
| Peters A |
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Peters |
Annette |
A |
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Institute for Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany. |
| Prokisch H |
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Prokisch |
Holger |
H |
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Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany. |
| Roden M |
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Roden |
Michael |
M |
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German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany. |
| Selvin E |
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Selvin |
Elizabeth |
E |
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Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins School of Medicine, USA. |
| Beekman M |
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Beekman |
Marian |
M |
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Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Department of Internal Medicine; Leiden University Medical Center, Leiden, Netherlands. |
| van Heemst D |
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van Heemst |
Diana |
D |
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Section of Gerontology and Geriatrics, Department of Internal Medicine; Leiden University Medical Center, Leiden, Netherlands. |
| Slagboom EP |
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Slagboom |
Eline P |
EP |
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Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Department of Internal Medicine; Leiden University Medical Center, Leiden, Netherlands. |
| Swenson BR |
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Swenson |
Brenton R |
BR |
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Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. |
| Tin A |
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Tin |
Adrienne |
A |
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Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA. |
| Tsai PC |
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Tsai |
Pei-Chien |
PC |
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Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan City, Taiwan. |
| Uitterlinden A |
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Uitterlinden |
Andre |
A |
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Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Visser WE |
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Visser |
W Edward |
WE |
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Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Völzke H |
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Völzke |
Henry |
H |
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Institute for Community Medicine; University Medicine Greifswald, Greifswald, Germany. |
| Waldenberger M |
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Waldenberger |
Melanie |
M |
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German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. |
| Walsh JP |
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Walsh |
John P |
JP |
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Medical School, University of Western Australia, Crawley, Australia. |
| Köttgen A |
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Köttgen |
Anna |
A |
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Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany. |
| Wilson SG |
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Wilson |
Scott G |
SG |
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School of Biomedical Sciences, University of Western Australia, Perth, Australia. |
| Peeters RP |
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Peeters |
Robin P |
RP |
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Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Bell JT |
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Bell |
Jordana T |
JT |
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Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, King's College London, London, United Kingdom. |
| Medici M |
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Medici |
Marco |
M |
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Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. |
| Teumer A |
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Teumer |
Alexander |
A |
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Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Thyroid : official journal of the American Thyroid Association |
| ISOABBREVIATION: Thyroid |
| YEAR: 2023 |
| MONTH: Mar |
| DAY: 01 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1557-9077 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Thyroid |
| COUNTRY: United States |
| ISSNLINKING: 1050-7256 |
| NLMUNIQUEID: 9104317 |
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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 |
| KLF9 |
| Mendelian randomization |
| gene expression |
| thyroid function |
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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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