Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference
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Published:2020-08-28
Issue:1
Volume:21
Page:
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ISSN:1474-760X
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Container-title:Genome Biology
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language:en
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Short-container-title:Genome Biol
Author:
Hop Paul J.ORCID, Luijk René, Daxinger Lucia, van Iterson Maarten, Dekkers Koen F., Jansen Rick, Heijmans Bastiaan T., ’t Hoen Peter A. C., van Meurs Joyce, Jansen Rick, Franke Lude, Boomsma Dorret I., Pool René, van Dongen Jenny, Hottenga Jouke J., van Greevenbroek Marleen M. J., Stehouwer Coen D. A., van der Kallen Carla J. H., Schalkwijk Casper G., Wijmenga Cisca, Zhernakova Sasha, Tigchelaar Ettje F., Slagboom P. Eline, Beekman Marian, Deelen Joris, van Heemst Diana, Veldink Jan H., van den Berg Leonard H., van Duijn Cornelia M., Isaacs Aaron, Uitterlinden André G., Jhamai P. Mila, Verbiest Michael, Suchiman H. Eka D., Verkerk Marijn, van der Breggen Ruud, van Rooij Jeroen, Lakenberg Nico, Mei Hailiang, van Iterson Maarten, Zhernakova Dasha V., van ’t Hof Peter, Deelen Patrick, ’t Hoen Peter A. C., Vermaat Martijn, Luijk René, Bonder Marc Jan, van Dijk Freerk, Arindrarto Wibowo, Kielbasa Szymon M., van Zwet Erik. W., ’t Hoen Peter-Bram, van Meurs Joyce B. J., ’t Hoen Peter A. C., Ikram M. Arfan, van Greevenbroek Marleen M. J., Boomsma Dorret I., Slagboom P. Eline, Veldink Jan H., van Zwet Erik W., Heijmans Bastiaan T.,
Abstract
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.
Funder
BBMRI-NL Netherlands CardioVascular Research Initiative
Publisher
Springer Science and Business Media LLC
Cited by
24 articles.
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