Conditionally independent (secondary) cis-eQTL signals were located further from the TSS (median distance 50.1 kb from the TSS, compared to 28.9 kb for primary eQTLs; Wilcoxon rank sum test, P ≤ 2.2×10−16). However, similar to primary eVariant associations, secondary eVariants were enriched for chromosomal contact with target eGene promoters, as determined through Hi-C, compared to background variant–TSS pairs (Supplementary Information 6). This suggests that, despite their sequence-based distance from the TSS, primary and secondary eVariants are in close physical contact with their target gene promoters via chromatin looping interactions. While primary eVariants were significantly more enriched in promoters than enhancers, secondary associations exhibit increased enhancer enrichment, consistent with their increased distance from the TSS and tissue-restricted activity (Wilcoxon rank sum test, P ≤ 2.2×10−16, Fig. 3c).
