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, Rick Jansen, Lude Franke, Dorret I. Boomsma, René Pool, Jenny van Dongen, Jouke J. Hottenga, Marleen M. J. van Greevenbroek, Coen D.A. Stehouwer, Carla Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Aaron Isaacs, André G. Uitterlinden, P. Mila Jhamai, Michaël Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Dasha V. Zhernakova, Peter van ‘t Hof, Patrick Deelen, Peter A.C. ’t Hoen, Martijn Vermaat, René Luijk, Marc Jan Bonder, Freerk van Dijk, Wibowo Arindrarto, Szymon M. Kiełbasa, Erik W. van Zwet, Peter A.C. ’t Hoen, Joyce B. J. van Meurs, Peter A.C. ’t Hoen, M. Arfan Ikram, Marleen M. J. van Greevenbroek, Dorret I. Boomsma, P. Eline Slagboom, Jan H. Veldink, Erik W. van Zwet, Bastiaan T. Heijmans
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), and NLRC5, 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.