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

  • Author(s): Pan, David Z
  • Garske, Kristina M
  • Alvarez, Marcus
  • Bhagat, Yash V
  • Boocock, James
  • Nikkola, Elina
  • Miao, Zong
  • Raulerson, Chelsea K
  • Cantor, Rita M
  • Civelek, Mete
  • Glastonbury, Craig A
  • Small, Kerrin S
  • Boehnke, Michael
  • Lusis, Aldons J
  • Sinsheimer, Janet S
  • Mohlke, Karen L
  • Laakso, Markku
  • Pajukanta, Päivi
  • Ko, Arthur
  • et al.
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.

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