We quantified the enrichment of trans-eVariants in promoter and enhancer regions using the same tissue-specific annotations from the Roadmap Epigenomics project1,2 used for cis-eQTL analysis (Extended Data Table 4). trans-eVariants (10% FDR) were enriched in cell-type matched enhancers (median Fisher’s exact test, P ≤ 2.2 ×10−3) but not strongly enriched for promoters (median P ≤ 0.22), compared to randomly selected variants matched by distance to nearest TSS, MAF and chromosome (Fig. 4b). trans-eVariants were more enriched than cis-eVariants at matched FDR (Wilcoxon rank sum test, promoter: P ≤ 4.6 ×10−7; enhancer: P ≤ 2.2 ×10−16). Stronger effect sizes are needed to detect trans-eVariants at the same FDR, but even comparing to a matched number of the strongest cis-eVariants, we observed greater enrichment in enhancer (but not promoter) regions among trans-eVariants, consistent with greater tissue-specificity of enhancer activity and trans-eVariants31 (Fig. 2c).
