Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9

Antoine Weihs; Layal Chaker; Tiphaine C Martin; Kim V E Braun; Purdey J Campbell; Simon R. Cox; Myriam Fornage; Christian Gieger; Hans J Grabe; Harald Grallert; Sarah Harris; Brigitte Kuhnel; Riccardo E Marioni; Nicholas Martin; Daniel L McCartney; Allan F. Mcrae; Christa Meisinger; Joyce B. J. van Meurs; Jana Nano; Matthias Nauck; Annette Peters; Holger Prokisch; Michael Roden; Elizabeth Selvin; Marian Beekman; Diana van Heemst; P Eline Slagboom; Brenton R. Swenson; Adrienne Tin; Pei-Chien Tsai; Andre G Uitterlinden; W. Edward Visser; Henry Völzke; Melanie Waldenberger; John P Walsh; Anna Köttgen; Scott G. Wilson; Robin P. Peeters; Jordana Tzenova Bell; Marco Medici; Alexander Teumer

doi:10.1089/thy.2022.0373

Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9

Antoine Weihs
, Layal Chaker
, Tiphaine C Martin
, Kim V E Braun
, Purdey J Campbell
, Simon R. Cox
, Myriam Fornage
, Christian Gieger
, Hans J Grabe
, Harald Grallert
, Sarah Harris
, Brigitte Kuhnel
, Riccardo E Marioni
, Nicholas Martin
, Daniel L McCartney
, Allan F. Mcrae
, Christa Meisinger
, Joyce B. J. van Meurs
, Jana Nano
, Matthias Nauck

Annette Peters, Holger Prokisch, Michael Roden, Elizabeth Selvin, Marian Beekman, Diana van Heemst, P Eline Slagboom, Brenton R. Swenson, Adrienne Tin, Pei-Chien Tsai, Andre G Uitterlinden, W. Edward Visser, Henry Völzke, Melanie Waldenberger, John P Walsh, Anna Köttgen, Scott G. Wilson, Robin P. Peeters, Jordana Tzenova Bell, Marco Medici, Alexander Teumer

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	301–311
Journal	Thyroid Journal Program
Volume	33
Issue number	3
Early online date	1 Mar 2023
DOIs	https://doi.org/10.1089/thy.2022.0373
Publication status	Published - 16 Mar 2023

Keywords / Materials (for Non-textual outputs)

thyroid function
DNA methylation
KLF9
Mendelian randomization
gene expression

Access to Document

10.1089/thy.2022.0373

WeihsEtalT2023Epigenome-wideAssociationStudyAccepted author manuscript, 308 KBLicence: Creative Commons: Attribution (CC-BY)

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Weihs, A., Chaker, L., Martin, T. C., Braun, K. V. E., Campbell, P. J., Cox, S. R., Fornage, M., Gieger, C., Grabe, H. J., Grallert, H., Harris, S., Kuhnel, B., Marioni, R. E., Martin, N., McCartney, D. L., Mcrae, A. F., Meisinger, C., van Meurs, J. B. J., Nano, J., ... Teumer, A. (2023). Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9. Thyroid Journal Program, 33(3), 301–311. https://doi.org/10.1089/thy.2022.0373

@article{324704c8f3a44bb2ad94f9ff5b35fa23,

title = "Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9",

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 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. ",

keywords = "thyroid function, DNA methylation, KLF9, Mendelian randomization, gene expression",

author = "Antoine Weihs and Layal Chaker and Martin, \{Tiphaine C\} and Braun, \{Kim V E\} and Campbell, \{Purdey J\} and Cox, \{Simon R.\} and Myriam Fornage and Christian Gieger and Grabe, \{Hans J\} and Harald Grallert and Sarah Harris and Brigitte Kuhnel and Marioni, \{Riccardo E\} and Nicholas Martin and McCartney, \{Daniel L\} and Mcrae, \{Allan F.\} and Christa Meisinger and \{van Meurs\}, \{Joyce B. J.\} and Jana Nano and Matthias Nauck and Annette Peters and Holger Prokisch and Michael Roden and Elizabeth Selvin and Marian Beekman and \{van Heemst\}, Diana and Slagboom, \{P Eline\} and Swenson, \{Brenton R.\} and Adrienne Tin and Pei-Chien Tsai and Uitterlinden, \{Andre G\} and Visser, \{W. Edward\} and Henry V{\"o}lzke and Melanie Waldenberger and Walsh, \{John P\} and Anna K{\"o}ttgen and Wilson, \{Scott G.\} and Peeters, \{Robin P.\} and Bell, \{Jordana Tzenova\} and Marco Medici and Alexander Teumer",

note = "Funding Information: H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care not related to this work. R.E.M. has received speaker fees from Illumina and is an advisor to the Epigenetic Clock Development Foundation. All other authors declare no conflicts of interest. ",

year = "2023",

month = mar,

day = "16",

doi = "10.1089/thy.2022.0373",

language = "English",

volume = "33",

pages = "301–311",

journal = "Thyroid Journal Program",

issn = "1050-7256",

publisher = "Mary Ann Liebert Inc.",

number = "3",

}

Weihs, A, Chaker, L, Martin, TC, Braun, KVE, Campbell, PJ, Cox, SR, Fornage, M, Gieger, C, Grabe, HJ, Grallert, H, Harris, S, Kuhnel, B, Marioni, RE, Martin, N, McCartney, DL, Mcrae, AF, Meisinger, C, van Meurs, JBJ, Nano, J, Nauck, M, Peters, A, Prokisch, H, Roden, M, Selvin, E, Beekman, M, van Heemst, D, Slagboom, PE, Swenson, BR, Tin, A, Tsai, P-C, Uitterlinden, AG, Visser, WE, Völzke, H, Waldenberger, M, Walsh, JP, Köttgen, A, Wilson, SG, Peeters, RP, Bell, JT, Medici, M & Teumer, A 2023, 'Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9', Thyroid Journal Program, vol. 33, no. 3, pp. 301–311. https://doi.org/10.1089/thy.2022.0373

TY - JOUR

T1 - Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9

AU - Weihs, Antoine

AU - Chaker, Layal

AU - Martin, Tiphaine C

AU - Braun, Kim V E

AU - Campbell, Purdey J

AU - Cox, Simon R.

AU - Fornage, Myriam

AU - Gieger, Christian

AU - Grabe, Hans J

AU - Grallert, Harald

AU - Harris, Sarah

AU - Kuhnel, Brigitte

AU - Marioni, Riccardo E

AU - Martin, Nicholas

AU - McCartney, Daniel L

AU - Mcrae, Allan F.

AU - Meisinger, Christa

AU - van Meurs, Joyce B. J.

AU - Nano, Jana

AU - Nauck, Matthias

AU - Peters, Annette

AU - Prokisch, Holger

AU - Roden, Michael

AU - Selvin, Elizabeth

AU - Beekman, Marian

AU - van Heemst, Diana

AU - Slagboom, P Eline

AU - Swenson, Brenton R.

AU - Tin, Adrienne

AU - Tsai, Pei-Chien

AU - Uitterlinden, Andre G

AU - Visser, W. Edward

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Walsh, John P

AU - Köttgen, Anna

AU - Wilson, Scott G.

AU - Peeters, Robin P.

AU - Bell, Jordana Tzenova

AU - Medici, Marco

AU - Teumer, Alexander

N1 - Funding Information: H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care not related to this work. R.E.M. has received speaker fees from Illumina and is an advisor to the Epigenetic Clock Development Foundation. All other authors declare no conflicts of interest.

PY - 2023/3/16

Y1 - 2023/3/16

N2 - 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 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.

AB - 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 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.

KW - thyroid function

KW - DNA methylation

KW - KLF9

KW - Mendelian randomization

KW - gene expression

U2 - 10.1089/thy.2022.0373

DO - 10.1089/thy.2022.0373

M3 - Article

SN - 1050-7256

VL - 33

SP - 301

EP - 311

JO - Thyroid Journal Program

JF - Thyroid Journal Program

IS - 3

ER -

Epigenome-wide association study reveals CpG sites associated with thyroid function and regulatory effects on KLF9

Abstract

Keywords / Materials (for Non-textual outputs)

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