We have reviewed approaches for the identification and interpretation of common-disease-associated variants that impact enhancer function, citing examples in which these methods have been successfully implemented (Figure 3, Table 2). We highlight three main conclusions. First, cell-type-specific enhancer variants are highly prevalent among loci associated with the majority of common diseases identified through GWASs. Second, GWAS-identified enhancer variants are disproportionally enriched in enhancer clusters, which control genes with highly specialized cell-type-specific functions. Third, these enhancer variants can have modest but significant effects on target gene expression, which can have robust effects on phenotype. Thus, interpreting the functional effects of enhancer variants requires rational experiment design that takes these characteristics into account. Furthermore, although current methods have enabled the thorough characterization of enhancer variants at some GWAS loci, high-throughput methods are needed, given the huge number of disease-associated enhancer variants. Here, we discuss additional lessons learned from these studies, and note five remaining challenges (Figure 4).
