1. Chromosomes and Gene Expression
  2. Human Biology and Medicine
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A promoter interaction map for cardiovascular disease genetics

  1. Lindsey E Montefiori  Is a corresponding author
  2. Debora R Sobreira
  3. Noboru J Sakabe
  4. Ivy Aneas
  5. Amelia C Joslin
  6. Grace T Hansen
  7. Grazyna Bozek
  8. Ivan P Moskowitz
  9. Elizabeth M McNally
  10. Marcelo A Nóbrega  Is a corresponding author
  1. University of Chicago, United States
  2. Northwestern University, United States
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Cite as: eLife 2018;7:e35788 doi: 10.7554/eLife.35788

Abstract

Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), however most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1,999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.

Article and author information

Author details

  1. Lindsey E Montefiori

    Department of Human Genetics, University of Chicago, Chicago, United States
    For correspondence
    lem@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-2342-6349
  2. Debora R Sobreira

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Noboru J Sakabe

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ivy Aneas

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amelia C Joslin

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Grace T Hansen

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Grazyna Bozek

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ivan P Moskowitz

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-0014-4963
  9. Elizabeth M McNally

    Center for Genetic Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Marcelo A Nóbrega

    Department of Human Genetics, University of Chicago, Chicago, United States
    For correspondence
    nobrega@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-0451-7846

Funding

National Institutes of Health (HL123857)

  • Marcelo A Nóbrega

National Institutes of Health (HL119967)

  • Marcelo A Nóbrega

National Institutes of Health (HL118758)

  • Marcelo A Nóbrega

National Institutes of Health (HL128075)

  • Elizabeth M McNally
  • Marcelo A Nóbrega

National Institutes of Health (T32GMOO7197)

  • Lindsey E Montefiori

American Heart Association (17PRE33410726)

  • Lindsey E Montefiori

National Institutes of Health (HL137307-01)

  • Lindsey E Montefiori

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Job Dekker, Reviewing Editor, University of Massachusetts Medical School, United States

Publication history

  1. Received: February 20, 2018
  2. Accepted: June 21, 2018
  3. Accepted Manuscript published: July 10, 2018 (version 1)

Copyright

© 2018, Montefiori et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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