Allele-specific enhancers mediate associations between LCAT and ABCA1 polymorphisms and HDL metabolism

PLoS One. 2019 Apr 30;14(4):e0215911. doi: 10.1371/journal.pone.0215911. eCollection 2019.

Abstract

For most complex traits, the majority of SNPs identified through genome-wide association studies (GWAS) reside within noncoding regions that have no known function. However, these regions are enriched for the regulatory enhancers specific to the cells relevant to the specific trait. Indeed, many of the GWAS loci that have been functionally characterized lie within enhancers that regulate expression levels of key genes. In order to identify polymorphisms with potential allele-specific regulatory effects, we developed a bioinformatics pipeline that harnesses epigenetic signatures as well as transcription factor (TF) binding motifs to identify putative enhancers containing a SNP with potential allele-specific TF binding in linkage disequilibrium (LD) with a GWAS-identified SNP. We applied the approach to GWAS findings for blood lipids, revealing 7 putative enhancers harboring associated SNPs, 3 of which lie within the introns of LCAT and ABCA1, genes that play crucial roles in cholesterol biogenesis and lipoprotein metabolism. All 3 enhancers demonstrated allele-specific in vitro regulatory activity in liver-derived cell lines. We demonstrated that these putative enhancers are in close physical proximity to the promoters of their respective genes, in situ, likely through chromatin looping. In addition, the associated alleles altered the likelihood of transcription activator STAT3 binding. Our results demonstrate that through our approach, the LD blocks that contain GWAS signals, often hundreds of kilobases in size with multiple SNPs serving as statistical proxies to the true functional site, can provide an experimentally testable hypothesis for the underlying regulatory mechanism linking genetic variants to complex traits.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics*
  • Alleles*
  • Base Sequence
  • Cell Line
  • Cholesterol, HDL / metabolism*
  • Chromatin / metabolism
  • Enhancer Elements, Genetic*
  • Genome-Wide Association Study
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Liver / metabolism
  • Phosphatidylcholine-Sterol O-Acyltransferase / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Promoter Regions, Genetic
  • Protein Binding
  • Response Elements / genetics
  • STAT3 Transcription Factor / metabolism

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Cholesterol, HDL
  • Chromatin
  • Interleukin-6
  • STAT3 Transcription Factor
  • LCAT protein, human
  • Phosphatidylcholine-Sterol O-Acyltransferase