Multiple enhancer variant loci associated with autoimmune diseases. (A) Variant Set Enrichment (VSE) analysis depicting enrichment of rheumatoid arthritis SNPs in putative enhancer elements in GM12878 cells. Boxplots represent the normalized null distribution generated using 1000 matched-random SNP sets. Diamonds correspond to the observed value relative to the null distribution. The red line denotes the threshold for significance, corrected for multiple testing. (B) Noncoding SNPs associated with rheumatoid arthritis. Shaded boxes denote instances where an H3K4me1 ChIP-seq peak detected in the indicated cell types overlaps either the GWAS lead SNP (listed to the right), or a SNP in LD with the lead SNP. The red boxes denote SNPs that drive the significant association with H3K4me1 sites in colon crypt and GM12878 cells. (C, left) Average H3K4me1 ChIP-seq signal at loci containing autoimmune disease-associated SNPs (red) and control H3K4me1 sites not associated with disease (black). (Right) H3K4me1 ChIP-seq signals at autoimmune disease-associated loci. Each row corresponds to an H3K4me1 site containing a SNP associated with any one of the six autoimmune diseases. (D) Same as C for H3K27ac. The dashed red line corresponds to the threshold of H3K27ac enrichment. (*) P < 0.004, Wilcoxon test (paired samples). (E) Same as C for DNase I hypersensitivity. The dashed red line corresponds to the threshold of DNase I HS. (F) Example of multiple enhancer variant locus associated with Crohn's disease. SNPs in LD with the lead SNP (rs762421) fall within multiple putative enhancer sites (gray boxes) enriched for H3K4me1 (black), DHS (purple), and H3K27ac (red). (G) Example of single enhancer variant locus associated with ulcerative colitis and Crohn's disease. Lead SNP (rs3024505) and LD SNPs fall in one enhancer (gray box). (H) Number of multiple enhancer variant loci and single enhancer variant loci detected for each of the six autoimmune traits. For example, for RA, 29 loci show evidence of multiple enhancer involvement, while seven show evidence of single enhancer involvement. (I) Bars display the number of GWAS loci in which the lead or LD SNP falls within coding regions (red), GM12878 putative enhancer elements (purple), and other (gray). Piecharts display the number of enhancers containing SNPs for each GWAS locus. (J) Percent of loci associated with all six autoimmune diseases showing evidence of multiple enhancer involvement in B lymphoblasts (red), compared with loci not known to be associated with a disease (gray). (**) P < 0.0001, by Fisher's exact test.