identification of loci that directly and indirectly contact enhancers of interest, and can reveal complex interactions in which dozens to hundreds of loci aggregate, so-called transcriptional hubs or enhanceosomes [65]. These types of high-order interactions have been recently described by several studies [55,56,58]. The extent by which they overlap risk loci remains unexplored. Unfortunately, these approaches tend to be expensive and difficult for most labs to execute, and their resolution often prohibits their use for interrogating GWAS loci. Until recently, for example, the resolution of Hi-C was limited to capturing interactions separated by more than one megabase; 5 to 10 times greater than the distance by which most enhancer-gene interactions occur. Despite the limitations, ‘C’-based methods have been implemented to successfully identify targets of enhancer-risk variants and to quantify their functional effects. For example, Cowper-Sal lari and colleagues utilized 3C and allele-specific expression to demonstrate the impact of the breast cancer risk SNP rs4784227 on expression of TOX3, thought to have a role in chromatin regulation [38]. Bauer and co-workers utilized 3C to identify BCL11A as the gene target of an erythroid enhancer, and then further demonstrated the impact of enhancer variants on transcription factor binding and expression. Gene editing
