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

Paul J. Hop; René Luijk; Lucia Daxinger; Maarten van Iterson; Koen F. Dekkers; Rick Jansen; Bastiaan T. Heijmans; Peter A.C. ’t Hoen; Joyce B. J. van Meurs; Lude Franke; Dorret Irene Boomsma; René Pool; Jenny van Dongen; Jouke‐Jan Hottenga; Marleen M. J. van Greevenbroek; Coen D.A. Stehouwer; Carla Kallen; Casper G. Schalkwijk; Cisca Wijmenga; Alexandra Zhernakova; Ettje F. Tigchelaar; P. Eline Slagboom; Marian Beekman; Joris Deelen; Diana van Heemst; Jan Herman Veldink; Leonard H. van den Berg; Cornelia M. van Duijn; Aaron J. Isaacs; André Gerardus Uitterlinden

doi:10.1186/s13059-020-02114-z

GenomicsGenome biologyAug 28, 2020

Peer-reviewed journal article

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

Paul J. Hop iD, René Luijk, Lucia Daxinger iD, Maarten van Iterson iD, Koen F. Dekkers iD, Rick Jansen iD, Bastiaan T. Heijmans iD, Peter A.C. ’t Hoen iD, Joyce B. J. van Meurs iD, Lude Franke iD, Dorret Irene Boomsma iD, René Pool iD, Jenny van Dongen iD, Jouke‐Jan Hottenga iD, Marleen M. J. van Greevenbroek iD, Coen D.A. Stehouwer iD, Carla Kallen iD, Casper G. Schalkwijk iD, Cisca Wijmenga iD, Alexandra Zhernakova iD, Ettje F. Tigchelaar, P. Eline Slagboom iD, Marian Beekman iD, Joris Deelen iD, Diana van Heemst iD, , M. Arfan Ikram iD

Abstract

DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identified 818 genes that influence DNA methylation patterns in blood using large-scale population genomics data. By employing genetic instruments as causal anchors, we identified directed associations between gene expression and distant DNA methylation levels, whilst ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. We found that DNA methylation patterns are commonly shaped by transcription factors that consistently increase or decrease DNA methylation levels. However, we also observed genes encoding proteins without DNA binding activity with widespread effects on DNA methylation (e.g. NFKBIE, CDCA7(L) and NLRC5) and we suggest plausible mechanisms underlying these findings. Many of the reported genes were unknown to influence DNA methylation, resulting in a comprehensive resource providing insights in the principles underlying epigenetic regulation.

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