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Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure

Author

Listed:
  • Marios Arvanitis

    (Johns Hopkins University
    Johns Hopkins University)

  • Emmanouil Tampakakis

    (Johns Hopkins University)

  • Yanxiao Zhang

    (Ludwig Institute for Cancer Research)

  • Wei Wang

    (23andMe, Inc.)

  • Adam Auton

    (23andMe, Inc.)

  • Diptavo Dutta

    (Johns Hopkins University
    Johns Hopkins Bloomberg School of Public Health)

  • Stephanie Glavaris

    (Johns Hopkins University)

  • Ali Keramati

    (Johns Hopkins University)

  • Nilanjan Chatterjee

    (Johns Hopkins Bloomberg School of Public Health
    Johns Hopkins University)

  • Neil C. Chi

    (University of California, San Diego
    University of California, San Diego)

  • Bing Ren

    (Ludwig Institute for Cancer Research
    University of California, San Diego)

  • Wendy S. Post

    (Johns Hopkins University
    Johns Hopkins Bloomberg School of Public Health)

  • Alexis Battle

    (Johns Hopkins University)

Abstract

Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure.

Suggested Citation

  • Marios Arvanitis & Emmanouil Tampakakis & Yanxiao Zhang & Wei Wang & Adam Auton & Diptavo Dutta & Stephanie Glavaris & Ali Keramati & Nilanjan Chatterjee & Neil C. Chi & Bing Ren & Wendy S. Post & Ale, 2020. "Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14843-7
    DOI: 10.1038/s41467-020-14843-7
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    Cited by:

    1. Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Matteo D’Antonio & Jennifer P. Nguyen & Timothy D. Arthur & Hiroko Matsui & Agnieszka D’Antonio-Chronowska & Kelly A. Frazer, 2023. "Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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