was shown to reduce enhancer activity by only 22% in vitro. Nonetheless, when the blond hair and ancestral alleles were evaluated in transgenic mice, the reduction in enhancer activity associated with the blond hair allele was sufficient to yield mice of visibly lighter coat color than mice generated with the ancestral allele [33]. Whether or not the blond-hair-associated SNP represents a special instance of a more general mechanism in which enhancer variants with modest functional effects have robust phenotypic effects remains to be seen.Table 2 Functional enhancer studies of GWAS risk loci Disease/trait Reference Lead SNP Proposed functional SNP Gene target How gene target was selected Cell type Data supporting SNP enhancer function Blond hair colorGuenther et al. [33]rs12821256rs12821256 KITLG Phenotype in mouse modelDeveloping hair follicles, HaCaT karatinocyte cell lineAllele-specific luciferase activity, allele-specific ChIP, effect of SNP on mouse phenotypeBreast cancerCowper-Sal lari et al. [38]rs4784227rs4784227 TOX3 3CMCF7Binding motif disruption, allele-specific ChIP, allele-specific 3C, allele-specific expression, eQTLColorectal cancerPomerantz et al. [34]rs6983267rs6983267 c-MYC 3CColo205 and LS174TAllele-specific luciferase activity, allele-specific ChIPColorectal cancerWright et al. [39]rs6983267rs6983267 c-MYC 3CDLD1 and HCT116Allele-specific ChIP, allele-specific expressionColorectal cancerTuupanen et al. [36]rs67491583rs67491583 c-MYC Nearest geneHeLaBinding motif disruption, allele-specific ChIP, allele-specific luciferase activityProstate cancerWasserman et al. [35]rs6983267rs6983267 c-MYC Nearest geneProstate
