DNase I sensitivity QTLs are a major determinant of human expression variation

Abstract

The mapping of expression quantitative trait loci (eQTLs) has emerged as an important tool for linking genetic variation to changes in gene regulation1-5. However, it remains difficult to identify the causal variants underlying eQTLs and little is known about the regulatory mechanisms by which they act. To address this gap, we used DNaseI sequencing to measure chromatin accessibility in 70 Yoruba lymphoblastoid cell lines (LCLs), for which genome-wide genotypes and estimates of gene expression levels are also available6-8. We obtained a total of 2.7 billion uniquely mapped DNase-seq reads, which allowed us to produce genome-wide maps of chromatin accessibility for each individual. We identified 9,595 locations at which DNase-seq read depth correlates significantly with genotype at a nearby SNP or indel (FDR=10%). We call such variants “DNaseI sensitivity Quantitative Trait Loci” (dsQTLs). We found that dsQTLs are strongly enriched within inferred transcription factor binding sites and are frequently associated with allele-specific changes in transcription factor binding. A substantial fraction (16%) of dsQTLs are also associated with variation in the expression levels of nearby genes, (namely, these loci are also classified as eQTLs). Conversely, we estimate that as many as 55% of eQTL SNPs are also dsQTLs. Our observations indicate that dsQTLs are highly abundant in the human genome, and are likely to be important contributors to phenotypic variation.