Fig. 3

Mechanisms underlying trans-meQLTs effects. a eQTL-mediated mechanism. If a SNP acts as an eQTL for a gene that regulates DNA methylation, the SNP can have an indirect effect on multiple CpG sites in trans. bCis-meQTL-mediated mechanism. If a SNP is a cis-meQTL for nearby CpG sites, which in turn impact the expression of genes involved in epigenetic regulatory processes, the SNP can ultimately alter DNA methylation levels at CpG sites in trans. c 3D organization mechanism. In the 3D genome, distal sites can move in close proximity, whereby a SNP can affect a DNA methylation levels at CpG sites in trans, acting either through cis-meQTL mechanisms, or by disrupting the formation of structural loops. d SNPs in the coding regions of methyl-specific binding proteins (such as MeCP2) can alter their specificity and function, and therefore passively or actively (by recruiting DNMTs or TETs) modify DNA methylation of their binding sites