A typical locus identified through a GWAS contains dozens to thousands of SNPs in linkage disequilibrium (LD) with the ‘lead’ SNP that is reported to be associated with the disease in question. Any SNP in LD with the lead SNP may be causal, and the prevailing assumption is that only one is causal. Indeed, this scenario has been reported to be the case for some risk loci involving enhancers [34,43], and there are several examples of Mendelian disorders in which a single enhancer variant causes congenital disease [44-50]. However, it is equally plausible that more than one SNP is causal, particularly at GWAS loci harboring enhancer clusters. In these instances, several variants distributed among multiple enhancers throughout the locus, rather than a single SNP, may combine to affect expression of their gene targets and confer susceptibility to common traits. This has been called the ‘multiple enhancer variant’ (MEV) hypothesis. Corradin and colleagues provided support for the MEV hypothesis for six common autoimmune disorders, including rheumatoid arthritis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus and ulcerative colitis. The extent of MEVs across additional common diseases is not yet known [7,28,37].
