Epigenome-Wide Association Study Reveals CpG Sites Associated with Thyroid Function and Regulatory Effects on KLF9
Thyroid, vol. 33, pp. 301–311
Abstract
Background: 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. Methods: 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). Results: Epigenome-wide significant associations ( p -value <1.1E-7) of three CpGs for free thyroxine, five for free triiodothyronine, and two for TSH concentrations were discovered and replicated (combined p -values = 1.5E-9 to 4.3E-28). The associations included CpG sites annotated to KLF9 (cg00049440) and DOT1L (cg04173586) that overlap with all three traits, consistent with hypothalamic–pituitary–thyroid axis physiology. Significant associations were also found for CpGs in FKBP5 for free thyroxine, and at CSNK1D/LINCO1970 and LRRC8D for free triiodothyronine. MR analyses supported a causal effect of thyroid status on DNA methylation of KLF9 . DNA methylation of cg00049440 in KLF9 was inversely correlated with KLF9 gene expression in blood. The CpG at CSNK1D/LINC01970 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 KLF9 , FKBP5 , LRRC8D , and CSNK1D/LINC01970 . Conclusions: 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 KLF9 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 in vitro and animal studies.
Authors 41
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Universitätsmedizin Greifswald · Universität Greifswald
Affiliation as printed
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
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Affiliation as printed
Erasmus MC Academic Center for Thyroid Diseases, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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St Thomas' Hospital · King's College London · Tisch Cancer Institute · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, King's College London, London, United Kingdom
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Affiliation as printed
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
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Affiliation as printed
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia
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Institute of Genetics and Cancer · University of Edinburgh
Affiliation as printed
Lothian Birth Cohorts, Department of Psychology; Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom
Institute of Genetics and Cancer
University of Edinburgh, Edinburgh, United Kingdom
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Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases · The University of Texas Health Science Center at Houston
Affiliation as printed
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, Texas, USA
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA
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Helmholtz Munich · German Centre for Cardiovascular Research
Affiliation as printed
German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Institute of Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
Research Unit Molecular Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
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Universitätsmedizin Greifswald · German Center for Neurodegenerative Diseases · Universität Greifswald
Affiliation as printed
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
German Centre for Neurodegenerative Diseases (DZNE), Site Rostock, Greifswald, Germany
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Affiliation as printed
Institute of Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
Research Unit Molecular Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
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Institute of Genetics and Cancer · University of Edinburgh
Affiliation as printed
Lothian Birth Cohorts, Department of Psychology; Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom
Institute of Genetics and Cancer
University of Edinburgh, Edinburgh, United Kingdom
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Affiliation as printed
Institute of Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
Research Unit Molecular Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
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Institute of Genetics and Cancer · University of Edinburgh
Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom
University of Edinburgh, Edinburgh, United Kingdom
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QIMR Berghofer Medical Research Institute
Affiliation as printed
QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Institute of Genetics and Cancer · University of Edinburgh
Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer; University of Edinburgh, Edinburgh, United Kingdom
University of Edinburgh, Edinburgh, United Kingdom
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The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia
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Affiliation as printed
Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany
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Affiliation as printed
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Orthopeadics and Sports Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Helmholtz Munich · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute for Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
Institute of Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
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Universitätsmedizin Greifswald · Universität Greifswald · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
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Helmholtz Munich · German Centre for Cardiovascular Research · Ludwig-Maximilians-Universität München
Affiliation as printed
German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Institute for Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
Institute of Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
Research Unit Molecular Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
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Helmholtz Munich · Institut für Humangenetik · Technical University of Munich
Affiliation as printed
Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany
Institute of Neurogenomics, Computational Health Center; Helmholtz Munich, Neuherberg, Germany
Helmholtz Munich, Neuherberg, Germany
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Deutsches Diabetes-Zentrum e.V. · German Center for Diabetes Research · Heinrich Heine University Düsseldorf
Affiliation as printed
Division of Endocrinology and Diabetology, Medical Faculty; Heinrich Heine University Düsseldorf, Düsseldorf, Germany
German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Medical Faculty; Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Marian Beekman Aachen Section of Molecular Epidemiology Department of Biomedical Data Sciences Department of Internal Medicine
Leiden University Medical Center
Affiliation as printed
Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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Diana van Heemst Aachen
Leiden University Medical Center
Affiliation as printed
Section of Gerontology and Geriatrics, Department of Internal Medicine; Leiden University Medical Center, Leiden, Netherlands
Leiden University Medical Center, Leiden, Netherlands
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P. Eline Slagboom Aachen Section of Molecular Epidemiology Department of Biomedical Data Sciences Department of Internal Medicine
Leiden University Medical Center
Affiliation as printed
Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA
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Johns Hopkins University · University of Mississippi Medical Center
Affiliation as printed
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
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St Thomas' Hospital · Chang Gung University · King's College London · Chang Gung Memorial Hospital · Taoyuan Chang Gung Memorial Hospital · Linkou Chang Gung Memorial Hospital
Affiliation as printed
Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, King's College London, London, United Kingdom
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
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Affiliation as printed
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Affiliation as printed
Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Universitätsmedizin Greifswald · Universität Greifswald · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Institute for Community Medicine; University Medicine Greifswald, Greifswald, Germany
Institute for Community Medicine
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Helmholtz Munich · German Centre for Cardiovascular Research
Affiliation as printed
German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Institute of Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
Research Unit Molecular Epidemiology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
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The University of Western Australia · Sir Charles Gairdner Hospital
Affiliation as printed
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia
Medical School, University of Western Australia, Crawley, Australia
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Johns Hopkins University · University of Freiburg
Affiliation as printed
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center—University of Freiburg, Freiburg, Germany
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St Thomas' Hospital · The University of Western Australia · King's College London · Sir Charles Gairdner Hospital
Affiliation as printed
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia
Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, King's College London, London, United Kingdom
School of Biomedical Sciences, University of Western Australia, Perth, Australia
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Affiliation as printed
Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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St Thomas' Hospital · King's College London
Affiliation as printed
Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital Campus, King's College London, London, United Kingdom
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Affiliation as printed
Erasmus MC Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Alexander Teumer corresponding
Medical University of Białystok · Universitätsmedizin Greifswald · Universität Greifswald · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
Institute for Community Medicine; University Medicine Greifswald, Greifswald, Germany
Institute for Community Medicine
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