Natural genetic variation quantitatively regulates heart rate and dimension

Jakob Gierten, Bettina Welz, Tomas Fitzgerald, Thomas Thumberger, Rashi Agarwal, Oliver Hummel, Adrien Leger, Philipp Weber, Kiyoshi Naruse, David Hassel, Norbert Hübner, Ewan Birney () and Joachim Wittbrodt ()
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Jakob Gierten: Heidelberg University
Bettina Welz: Heidelberg University
Tomas Fitzgerald: European Bioinformatics Institute (EMBL-EBI)
Thomas Thumberger: Heidelberg University
Rashi Agarwal: 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
Norbert Hübner: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Ewan Birney: European Bioinformatics Institute (EMBL-EBI)
Joachim Wittbrodt: Heidelberg University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59425-7

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