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Natural genetic variation quantitatively regulates heart rate and dimension

Author

Listed:
  • Jakob Gierten

    (Heidelberg University
    Heidelberg University Hospital
    German Centre for Cardiovascular Research (DZHK); Partner Site Heidelberg/Mannheim)

  • Bettina Welz

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK); Partner Site Heidelberg/Mannheim
    Heidelberg University)

  • Tomas Fitzgerald

    (European Bioinformatics Institute (EMBL-EBI))

  • Thomas Thumberger

    (Heidelberg University)

  • Rashi Agarwal

    (Heidelberg University
    Heidelberg University)

  • Oliver Hummel

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Adrien Leger

    (European Bioinformatics Institute (EMBL-EBI))

  • Philipp Weber

    (Heidelberg University Hospital)

  • Kiyoshi Naruse

    (National Institutes of Natural Sciences)

  • David Hassel

    (German Centre for Cardiovascular Research (DZHK); Partner Site Heidelberg/Mannheim
    Heidelberg University Hospital)

  • Norbert Hübner

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    German Center for Cardiovascular Research (DZHK); Partner Site Berlin
    Charité-Universitätsmedizin Berlin
    Helmholtz Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University)

  • Ewan Birney

    (European Bioinformatics Institute (EMBL-EBI))

  • Joachim Wittbrodt

    (Heidelberg University
    German Centre for Cardiovascular Research (DZHK); Partner Site Heidelberg/Mannheim)

Abstract

The polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models, Oryzias latipes, and Oryzias sakaizumii. Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In an F2 segregation population of 1192 HO5 x HdrR embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes by gene editing revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart.

Suggested Citation

  • Jakob Gierten & Bettina Welz & Tomas Fitzgerald & Thomas Thumberger & Rashi Agarwal & Oliver Hummel & Adrien Leger & Philipp Weber & Kiyoshi Naruse & David Hassel & Norbert Hübner & Ewan Birney & Joac, 2025. "Natural genetic variation quantitatively regulates heart rate and dimension," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59425-7
    DOI: 10.1038/s41467-025-59425-7
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    References listed on IDEAS

    as
    1. Kristjan Norland & Gardar Sveinbjornsson & Rosa B. Thorolfsdottir & Olafur B. Davidsson & Vinicius Tragante & Sridharan Rajamani & Anna Helgadottir & Solveig Gretarsdottir & Jessica Setten & Folkert W, 2019. "Sequence variants with large effects on cardiac electrophysiology and disease," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Hannah V. Meyer & Timothy J. W. Dawes & Marta Serrani & Wenjia Bai & Paweł Tokarczuk & Jiashen Cai & Antonio Marvao & Albert Henry & R. Thomas Lumbers & Jakob Gierten & Thomas Thumberger & Joachim Wit, 2020. "Genetic and functional insights into the fractal structure of the heart," Nature, Nature, vol. 584(7822), pages 589-594, August.
    Full references (including those not matched with items on IDEAS)

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