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Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Zheng, S.L. ; Vasan, R.S. ; Smith, J.G. LU orcid ; Vasan, Ramachandran S. and Lumbers, R.T. (2024) In Nature Genetics 56. p.2646-2658
Abstract
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing... (More)
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics. © The Author(s) 2024. (Less)
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Contribution to journal
publication status
published
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in
Nature Genetics
volume
56
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85210019601
  • pmid:39572783
ISSN
1061-4036
DOI
10.1038/s41588-024-01952-y
language
English
LU publication?
yes
id
8c844112-44d9-4a7f-aa29-203de8397d41
date added to LUP
2025-10-13 13:24:38
date last changed
2025-10-17 11:07:36
@article{8c844112-44d9-4a7f-aa29-203de8397d41,
  abstract     = {{Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics. © The Author(s) 2024.}},
  author       = {{Zheng, S.L. and Vasan, R.S. and Smith, J.G. and Vasan, Ramachandran S. and Lumbers, R.T.}},
  issn         = {{1061-4036}},
  language     = {{eng}},
  pages        = {{2646--2658}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy}},
  url          = {{http://dx.doi.org/10.1038/s41588-024-01952-y}},
  doi          = {{10.1038/s41588-024-01952-y}},
  volume       = {{56}},
  year         = {{2024}},
}