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 NauckAnnette 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 journalArticlepeer-review

Abstract / Description of output

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 languageEnglish
Pages (from-to)301–311
JournalThyroid Journal Program
Issue number3
Early online date1 Mar 2023
Publication statusPublished - 16 Mar 2023

Keywords / Materials (for Non-textual outputs)

  • thyroid function
  • DNA methylation
  • KLF9
  • Mendelian randomization
  • gene expression


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