Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver

Am J Hum Genet. 2019 Jul 3;105(1):89-107. doi: 10.1016/j.ajhg.2019.05.010. Epub 2019 Jun 13.


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.

Keywords: CAPTURE-C; ChIP-seq; DNA-looping; GWAS; RNA-seq; eQTL; fine mapping; gene regulation; hQTL; liver.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Chromosome Mapping / methods*
  • Epigenesis, Genetic*
  • Female
  • Genetic Association Studies
  • Hep G2 Cells
  • Histones / genetics
  • Humans
  • Liver / metabolism
  • Liver / pathology*
  • Male
  • Middle Aged
  • Multifactorial Inheritance / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Prospective Studies
  • Quantitative Trait Loci*
  • Regulatory Sequences, Nucleic Acid
  • Young Adult


  • Chromatin
  • Histones
  • histone H3 trimethyl Lys4