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

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

Author information

1
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
2
Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, 90095, USA.
3
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
4
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22904, USA.
5
Big Data Institute, University of Oxford, Oxford, OX3 7LF, UK.
6
Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
7
Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
8
Department of Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
9
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, FI-70210, Kuopio, Finland.
10
Molecular Biology Institute at UCLA, Los Angeles, CA, 90095, USA.
11
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. a5ko@ucla.edu.
12
Molecular Biology Institute at UCLA, Los Angeles, CA, 90095, USA. a5ko@ucla.edu.

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.

PMID:
29666371
PMCID:
PMC5904163
DOI:
10.1038/s41467-018-03554-9
[Indexed for MEDLINE]
Free PMC Article

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