Impact of multiple enhancer variants on gene expression. (A) UCSC Genome Browser image of multiple enhancer variant locus associated with ulcerative colitis. Red arrow indicates lead SNP (rs4728142). FPKMs (fragments per kilobase per million reads) of the predicted target transcript IRF5 and nonpredicted transcript TNPO3 based on SNP genotype at the ulcerative colitis locus are shown (bottom). Gray Tukey plots display the normal range of expression for each gene. (B) Percent of GWAS loci with transcripts that show differential gene expression based on SNP genotype at single (left) and multiple (right) enhancer variant loci. Enhancer SNPs linked to a gene target using PreSTIGE are shown in purple and red. Controls include the expressed gene nearest the SNP that is not a PreSTIGE-predicted target (gray) and a randomly selected expressed gene (within 500 kb) that is not a PreSTIGE-predicted target (black) (Fisher's exact test). (C) Percent of GWAS loci associated with differential gene expression for single enhancer variant loci (purple) versus all multiple enhancer variant loci (red) and loci with more than four enhancers with variants (black) (Fisher's exact test). (D–G) Expression of transcripts in B-lymphoblasts derived from individuals carrying the risk allele compared with those homozygous for the nonrisk allele for four representative loci. Gray Tukey plots display the normal range of expression for each gene. “rs” numbers correspond to the lead SNPs at each GWAS locus (Mann-Whitney-Wilcoxon test). (*) P < 0.02, (**) P < 0.007, (***) P < 0.0001.