Genetic and phenotypic architecture of human myocardial trabeculation
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.
Authors
- Antônio H. Ribeiro (ORCID: https://orcid.org/0000-0003-3632-8529)
- Albert Henry (ORCID: https://orcid.org/0000-0001-7422-2288)
- James S. Ware (ORCID: https://orcid.org/0000-0002-6110-5880)
- Sean L. Zheng (ORCID: https://orcid.org/0000-0002-5762-6392)
- Mengyun Qiao (ORCID: https://orcid.org/0000-0002-5157-1079)
- Arunashis Sau (ORCID: https://orcid.org/0000-0002-0204-7078)
- Wenjia Bai (ORCID: https://orcid.org/0000-0003-2943-7698)
- Declan P. O’Regan (ORCID: https://orcid.org/0000-0002-0691-0270)
- Fu Siong Ng (ORCID: https://orcid.org/0000-0002-8681-4368)
- Kathryn A. McGurk (ORCID: https://orcid.org/0000-0002-5445-6906)
- R Thomas Lumbers (ORCID: https://orcid.org/0000-0002-9077-4741)
- Antônio Luiz Pinho Ribeiro (ORCID: https://orcid.org/0000-0002-0364-3584)
Institutions
- Broad Institute (US)
- Uppsala University (SE)
- Imperial College Healthcare NHS Trust (GB)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- Chelsea and Westminster Hospital NHS Foundation Trust (GB)
- Harefield Hospital (GB)
- National Institute for Health and Care Research (GB)
- Lung Institute (US)
- Hospital das Clínicas da Universidade Federal de Minas Gerais (BR)
- MRC London Institute of Medical Sciences (GB)
- University College London (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s44161-024-00564-3
- Citations
- 8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Foundation for the National Institutes of Health
- Wellcome
- National Institute for Health and Care Research
- British Heart Foundation
- Sir Jules Thorn Charitable Trust
- Imperial College London
- University College London
- National Heart and Lung Institute
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institutes of Health
- Medical Research Council
- Engineering and Physical Sciences Research Council