Despite a long appreciation of the involvement of regulatory variants in human disease (32-34), difficulty in delineating regulatory DNA regions, particularly in a cell-specific context, has heretofore prevented comprehensive assessment of the relationship between gene regulation and common phenotypes. Our results indicating widespread and systematic localization of variants associated with a wide spectrum of common diseases and traits in regulatory DNA marked by DHSs have many implications for interpreting diverse genotype-phenotype association studies. The connection of numerous DHSs harboring GWAS SNPs with promoters of distant genes expands the genomic horizon of disease and trait associations, and provides a trove of plausible causal genes to explain those associations. The data also unify seemingly unconnected variants associated with related diseases by virtue of their convergent perturbation of common transcription factor networks. Tissue-selective enrichment of phenotype-associated variants raises the possibility of more focused genetic association studies that condition on the regulatory DNA of a known or hypothesized target tissue type. Further, selective enrichment of many more weakly-associated variants within regulatory DNA of pathogenic cell types points to the quantitative contribution of hundreds of
