Genetic effects on chromatin accessibility uncover mechanisms of liver gene regulation and quantitative traits

Chromatin accessibility quantitative trait locus (caQTL) studies have identified regulatory elements that underlie genetic effects on gene expression and metabolic traits. However, caQTL discovery has been limited by small sample sizes. Here, we mapped caQTLs in liver tissue from 138 human donors and identified caQTLs for 35,361 regulatory elements, including population-specific caQTLs driven by differences in allele frequency across populations. We identified 2,126 genetic signals associated with multiple, presumably coordinately regulated elements. Coordinately regulated elements linked distal elements to target genes and were more likely to be associated with gene expression compared to single-element caQTLs. We predicted driver and response elements at coordinated loci and found that driver elements were enriched for transcription factor binding sites of key liver regulators. We identified colocalized caQTLs at 667 genome-wide association (GWAS) signals for metabolic and liver traits and annotated these loci with predicted target genes and disrupted transcription factor binding sites. CaQTLs identified three-fold more GWAS colocalizations than liver expression QTLs (eQTLs) in a larger sample size, suggesting that caQTLs can detect mechanisms missed by eQTLs. At a GWAS signal colocalized with a caQTL and an eQTL for TENM2, we validated regulatory activity for a variant within a predicted driver element that was coordinately regulated with 39 other elements. At another locus, we validated a predicted enhancer of RALGPS2 using CRISPR interference and demonstrated allelic effects on transcription for a haplotype within this enhancer. These results demonstrate the power of caQTLs to characterize regulatory mechanisms at GWAS loci.