Lastly, genes are frequently regulated by multiple enhancer elements or clusters of enhancer elements. Thus, the independent effect of a single enhancer or variant may be below the sensitivity threshold of standard assays. This, in addition to the demonstration that multiple enhancer SNPs can act in combination to impact gene expression, suggests that epistatic effects between noncoding variants may play a particularly important role for enhancer loci, especially when enhancer variants of the same gene are inherited independently. The impact of the interaction between SNPs on transcription and ultimately on clinical risk for disease remains to be seen.
