Natural genetic variation quantitatively regulates heart rate and dimension
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 automa...
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| Hauptverfasser: | , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
30 April 2025
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| In: |
Nature Communications
Year: 2025, Jahrgang: 16, Pages: 1-12 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-59425-7 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-59425-7 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-59425-7 
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| Verfasserangaben: | Jakob Gierten, Bettina Welz, Tomas Fitzgerald, Thomas Thumberger, Rashi Agarwal, Oliver Hummel, Adrien Leger, Philipp Weber, Kiyoshi Naruse, David Hassel, Norbert Hübner, Ewan Birney & Joachim Wittbrodt |
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| 245 | 1 | 0 | |a Natural genetic variation quantitatively regulates heart rate and dimension |c Jakob Gierten, Bettina Welz, Tomas Fitzgerald, Thomas Thumberger, Rashi Agarwal, Oliver Hummel, Adrien Leger, Philipp Weber, Kiyoshi Naruse, David Hassel, Norbert Hübner, Ewan Birney & Joachim Wittbrodt |
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| 520 | |a 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. | ||
| 650 | 4 | |a Cardiovascular genetics | |
| 650 | 4 | |a Congenital heart defects | |
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| 650 | 4 | |a Genetic linkage study | |
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