Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.
Zheng, Sean L Henry, Albert Cannie, Douglas Lee, Michael Miller, David McGurk, Kathryn A Bond, Isabelle Xu, Xiao Issa, Hanane Francis, Catherine
Zheng, Sean L
Henry, Albert
Cannie, Douglas
Lee, Michael
Miller, David
McGurk, Kathryn A
Bond, Isabelle
Xu, Xiao
Issa, Hanane
Francis, Catherine
Series / Report no.
Open Access
Type
Article
Language
en
Date of publication
2024-11-21
Year of publication
Research Projects
Organizational Units
Journal Issue
Title
Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.
Translated Title
Published in
Nat Genet 2024; 56(12):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 strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.