Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

Paul J. Hop, Rene Luijk, Lucia Daxinger, Maarten van Iterson, Koen F. Dekkers, Rick Jansen, Joyce B. J. van Meurs, Peter A. C. 't Hoen, M. Arfan Ikram, Marleen M. J. van Greevenbroek, Dorret Boomsma, P. Eline Slagboom, Jan H. Veldink, Erik W. van Zwet, Bastiaan T. Heijmans*, BIOS Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. Results By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g.,NFKBIE,CDCA7(L), andNLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation. Conclusion We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.

Original languageEnglish
Article number220
Number of pages24
JournalGenome Biology
Volume21
Issue number1
DOIs
Publication statusPublished - 28 Aug 2020

Keywords

  • DNA methylation
  • Epigenetic regulation
  • Transcription factor
  • Chromatin
  • Genetic instrumental variable
  • Functional genomics
  • Pleiotropy
  • Causal inference
  • NETHERLANDS TWIN REGISTER
  • EMBRYONIC STEM-CELLS
  • TRANSCRIPTION FACTORS
  • INTEGRATIVE ANALYSIS
  • GENOTYPE DATA
  • SEQUENCE
  • ASSOCIATION
  • RECRUITMENT
  • CHROMATIN
  • FORMAT

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