Abstract
Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 74 GWAS loci that have been associated with at least one complex phenotype. Our results reveal a repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.
Highlights
The liver has a central role in detoxification of endogenous and exogenous toxins, synthesis of essential proteins, and regulation of carbohydrate, lipid, and drug metabolism
We quantify regulatory element activity in the human liver across multiple individuals and integrate these findings with genome-wide gene expression data collected from the same human liver tissues, high-resolution promoterfocused chromatin interaction maps collected from human liver-derived HepG2 cells, and genome-wide association studies (GWASs) summary statistics for 20 commonly studied phenotypes with variable levels of suggested causality manifesting in the liver.[2]
When lead histone QTLs (hQTLs) and lead GWAS variants were in high linkage disequilibrium (r2 > 0.8), we considered such hQTL-peaks as the likely trait-relevant regulatory elements in GWAS loci. r2 was calculated in the 1000 Genomes, Phase 3, European population
Summary
The liver has a central role in detoxification of endogenous and exogenous toxins, synthesis of essential proteins, and regulation of carbohydrate, lipid, and drug metabolism. Discovering genotype-dependent non-coding functional activity can help to fine map and reveal mechanisms underlying complex trait associations.[7,8,9,10,11,12,13,14] Performing such studies at genome-wide scale in large numbers of human tissues is challenging[15] and has been limited to those performed in accessible lymphoblastoid cell lines or blood cell types.[16,17,18,19,20,21,22] Here, we quantify regulatory element activity in the human liver across multiple individuals and integrate these findings with genome-wide gene expression data collected from the same human liver tissues, high-resolution promoterfocused chromatin interaction maps collected from human liver-derived HepG2 cells, and GWAS summary statistics for 20 commonly studied phenotypes with variable levels of suggested causality manifesting in the liver.[2] We identify 2,625 genes and 972 regulatory elements with genotype-dependent activity in the human liver and finemap a total of 74 GWAS loci that have been associated with at least one complex phenotype. We provide a unique resource that contributes to basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue and highlight the benefits of integrating multiple cellular traits for the identification and characterization of disease-relevant genes, regulatory elements, and variants
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