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.

中文翻译：

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使用基因锚进行因果推断，对调节 DNA 甲基化的基因进行全基因组鉴定


背景 DNA 甲基化是人类发育和疾病中的关键表观遗传修饰，但对其高度协调的调控了解有限。在这里，我们利用大规模群体基因组数据确定了影响血液中 DNA 甲基化模式的 818 个基因。结果通过使用遗传工具作为因果锚点，我们在基因表达和远距离DNA甲基化水平之间建立了直接关联，同时通过校正邻近基因之间的连锁不平衡和多效性来确保关联的特异性。已鉴定的基因富含转录因子，其中许多转录因子在多个 CpG 位点上持续升高或降低 DNA 甲基化水平。此外，我们发现大量转录因子影响其实验确定的结合位点的 DNA 甲基化。我们还观察到编码具有异源功能的蛋白质的基因，这些蛋白质对DNA甲基化具有广泛的影响，例如NFKBIE、CDCA7(L)和NLRC5，并且对于几个例子，我们提出了它们对DNA甲基化影响的合理机制。结论 我们报告了数百个影响 DNA 甲基化的基因，并提供了表观遗传调控原理的重要见解。