Cis-acting genetic–epigenetic interactions can lead to inter-individual differences in DNA looping, gene expression, and disease susceptibility. Simplified representations of three-dimensional chromatin structure in haplotype blocks containing genome wide association study (GWAS) peaks, highlighting the potential effects of regulatory sequence variants (rSNPs) on DNA methylation, interactions between regulatory elements (insulators, enhancers and promoters), topologically associating domain (TAD) structures, gene expression, and disease susceptibility. a CTCF-mediated chromatin looping leading to formation of “active” and “inactive” TADs. Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and Hi-C have mapped chromatin interactions and have identified TADs as large-scale chromatin structures, with CTCF or cohesin enriched at the TAD boundaries [103]. The chromatin loops promote intra-domain interactions between regulatory elements, such as enhancers and gene promoters (which induce gene expression), while preventing inter-domain contacts in order to minimize promiscuous gene expression. In this model, regulatory variants at TAD boundaries or intra-domain contacts (sub-TAD boundaries) can induce high- or low-order chromatin configuration changes that disrupt the insulated neighborhoods formed by the looping, thereby causing either the abolition of enhancer–promoter interactions (in active TADs) or the formation of ectopic enhancer–promoter interactions (in inactive TADs). Additionally, regulatory variants at active transcription factor (TF)-bound enhancers can directly affect enhancer–promoter interactions. Variants that affect the integrity of TAD structures and chromatin interactions are more likely to have functional effects and to be rSNPs, which can sometimes lead to disease susceptibility. b Chromatin looping leads to active or inactive insulated chromatin neighborhoods, which can vary between individuals because of haplotype-dependent allele-specific DNA methylation (hap-ASM) rSNPs and can therefore influence DNA methylation patterns and disease susceptibility. In this genomic configuration (AA alleles at the enhancer SNP of gene X, AA alleles at the CTCF-binding site SNP of the gene-X-containing loop, and AA alleles at the CTCF-binding site SNP of the gene-Y-containing loop), both of the TAD anchor sites have a high affinity for CTCF. In the chromatin loop associated with gene X, the formation of the loop brings the enhancer and promoter into close proximity. The active enhancer is bound by TFs and RNA polymerase interacts with the gene X promoter to induce transcription [122, 189]. Conversely, the chromatin loop containing gene Y enforces gene silencing by isolating the promoter away from neighboring enhancers. CTCF and TF occupancy is associated with low methylation at the TAD anchor sites and in enhancer sequences, expression of gene X, silencing of gene Y, and no disease susceptibility. c In this configuration (BB at the enhancer SNP of gene X, AA at the CTCF-binding site SNP of the gene-X-containing loop, and AA at the CTCF-binding site SNP of the gene-Y-containing loop), the anchor sites bind CTCF with high affinity. Although the CTCF-anchored loops are not altered, the rSNP at the enhancer of gene X disrupts the binding of the TF and RNAPII complex, resulting in a high methylation level at the enhancer and gene silencing. In this scenario, the silencing of gene X leads to disease susceptibility, associated with the GWAS index SNP allele BB, which is in linkage disequilibrium (LD) with the functional rSNP allele BB at the enhancer of gene X. d In this configuration (AA at the enhancer SNP of gene X, BB at the CTCF-binding site SNP of the gene-X-containing loop, and AA at the CTCF-binding site SNP of the gene-Y-containing loop), allele BB at the CTCF-dependent TAD anchor site associated with gene X leads to a low affinity for CTCF. The loss of CTCF binding disrupts the higher-order chromatin loop, and the promoter–enhancer interaction of gene X is no longer facilitated, although TF binding is not altered at the enhancer. e In this configuration (AA at the enhancer SNP of gene X, AA at the CTCF-binding site SNP of the gene-X-containing loop, BB at the CTCF-binding site SNP of the gene-Y-containing loop), allele BB at the CTCF-mediated TAD anchor site of the gene-Y-containing loop has a low affinity for CTCF. The loss of CTCF binding disrupts the chromatin loop, such that the promoter of gene Y is no longer isolated from the active enhancer of the neighboring expressed gene, which induces an ectopic enhancer–promoter interaction. This loss of CTCF occupancy is associated with a high methylation level at one of the anchor sites of gene-Y-containing TAD, and expression of gene Y. In this scenario, the expression of gene Y leads to a disease phenotype associated with the GWAS peak SNP allele BB, which is in LD with the causal rSNP allele BB at the CTCF-binding site