Genetic and phenotypic architecture of human myocardial trabeculation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their
development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. Here
we report variant associations across the allele frequency spectrum for trabecular morphology in 47,803
participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an
association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and
ventricular development. Genome-wide association studies identified 68 loci in pathways that regulate
sarcomeric function, differentiation of the conduction system, and cell fate determination. We found that
trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in
hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease
expression.
development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. Here
we report variant associations across the allele frequency spectrum for trabecular morphology in 47,803
participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an
association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and
ventricular development. Genome-wide association studies identified 68 loci in pathways that regulate
sarcomeric function, differentiation of the conduction system, and cell fate determination. We found that
trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in
hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease
expression.
Date Issued
2024-12
Date Acceptance
2024-10-22
Citation
Nature Cardiovascular Research, 2024, 3 (12)
ISSN
2731-0590
Publisher
Springer Nature
Journal / Book Title
Nature Cardiovascular Research
Volume
3
Issue
12
Copyright Statement
© The Author(s) 2024 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.nature.com/articles/s44161-024-00564-3
Publication Status
Published
Date Publish Online
2024-11-20