To further examine the enrichment of GWAS SNPs in regulatory DNA, we systematically classified all noncoding GWAS SNPs by the quality of their experimental replication. This disclosed 2,436 unreplicated SNPs; 2,374 ‘internally-replicated’ SNPs (confirmed in a second population in the initial publication); and 324 ‘externally-replicated’ SNPs (confirmed in an independent study) (table S2) (12). We observed a monotonic increase in the proportion of disease/trait variants localizing in DHSs with increasing quality of GWAS SNP experimental replication (Fig. 1B), as well as with increasing strength of association and study sample size (fig. S3). For externally replicated noncoding SNPs, 69.8% lie within a DHS (n=226, P < 10-14, simulation, fig. S2). To exclude the influence of population stratification, we compared the fixation index in African and European populations between GWAS SNPs in DHSs and matched SNPs not in DHSs and found them to be nearly identical (FST=0.0843 vs. 0.0847, respectively) (12). The monotonic relationship between evidence for association and SNP concentration in DHSs strongly suggests that many variants are functional and that unreplicated or weaker associations may obscure the true degree of enrichment in DHSs.
