Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS

Nat Commun. 2018 Apr 17;9(1):1512. doi: 10.1038/s41467-018-03554-9.

Abstract

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi-C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / metabolism*
  • Adipose Tissue / cytology
  • Adiposity / genetics*
  • Aged
  • Body Mass Index
  • Cells, Cultured
  • Chromosomes, Human / genetics*
  • Cohort Studies
  • Finland
  • Gene Expression Regulation / physiology
  • Gene Library
  • Gene Regulatory Networks / physiology
  • Genetic Predisposition to Disease*
  • Genomics / methods
  • Humans
  • Male
  • Middle Aged
  • Obesity / genetics*
  • Obesity / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Primary Cell Culture
  • Promoter Regions, Genetic / genetics
  • Quantitative Trait Loci / genetics