Many disease-associated SNPs are located outside of protein-coding exons and a large proportion of human genes display expression polymorphism28. Using the NHGRI GWAS catalog29 and extending the compilation of lead SNPs with proxy SNPs in strong linkage disequilibrium (similar to refs. 30,31), we identified diseases/traits whose associated SNPs overlapped enhancers, promoters, exons and random regions significantly more than expected by chance (Fisher's Exact Test P<0.01, Supplementary Table 16). Disease-associated SNPs were over-represented in regulatory regions to a greater extent than in exons (Fig. 6c). For many traits where enriched disease-associated SNPs were within enhancers, enhancer activity was detected in pathologically relevant cell types (Fig. 6d, and Supplementary Figs 31 and 32). Examples include Graves’ disease-associated SNPs enriched in enhancers that are expressed predominantly in thyroid tissue, and similarly lymphocytes for chronic lymphocytic leukemia. As a proof of concept, we validated the impact of two disease-associated regulatory SNPs within enhancers (Supplementary Fig. 33).
