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

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.

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Journal
Nature Genetics
Published
2024-11-21
DOI
https://doi.org/10.1038/s41588-024-01952-y
Citations
48
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
11.22

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article

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

Jeffrey Brandimarto, Albert Henry, James Moon, Anna Axelsson Raja et al.
48 citations
Nature Genetics
RNA modifications and cancer
11.22
article

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

Jeffrey Brandimarto, Albert Henry, James Moon, Anna Axelsson Raja, Kenneth B. Margulies, Ramachandran Srini Vasan, Perry Elliott, Christopher M. Haggerty, Erik Abner, J. G. Smith, Søren Brunak, Lori Morton, Alex S. F. Doney, Mahdad Noursadeghi, Philippe Charron, Lars Lind, Henrik Ullum, Kāri Stefánsson, Petros Syrris, James S. Ware, Vilmantas Giedraitis, Marie‐Pierre Dubé, Antonios Pantazis, Brandon D. Lowery, Svati H. Shah, Eric Farber‐Eger, Paul J.R. Barton, Ana M. Valdes, Thomas P. Cappola, Catherine Francis, Sean L. Zheng, Akshay Shekhar, Pantazis Theotokis, Hans L. Hillege, Thomas A. Treibel, Rachel Buchan, Brian P. Halliday, Upasana Tayal, Douglas Ewan Cannie, ANJALI TIKU OWENS, Eric Villard, Folkert W. Asselbergs, W. M. Monique Verschuren, Daníel F. Guðbjartsson, Doug Speed, Krishna G. Aragam, Johan Ärnlöv, Hanane Issa, Ify Mordi, Lance Adams, Charlotte Manisty, Sundararajan Srinivasan, Maris Teder‐Laving, Cecilia M. Lindgren, Jean‐François Deleuze, Isabella Kardys, Michela Noseda, Henning Bundgaard, Ole Birger Pedersen, Xiao Yun Xu, Quinn S. Wells, Diane T. Smelser, Jonas Ghouse, Sisse Rye Ostrowski, Sanjay Prasad, Chim C. Lang, Declan P. O’Regan, Patrick T. Ellinor, David‐Alexandre Trégouët, Stuart A. Cook, Antonio de Marvao, Spiros Denaxas, Christian Erikstrup, D.J. Miller, Andrew D. Morris, Michael P. Morley, Vinicius Tragante, Kathryn A. McGurk, Aroon D. Hingorani, Anna Helgadóttir, Hilma Hólm, Chris Finan, R Thomas Lumbers, Kiran J. Biddinger, Joshua Backman, Eric H. Boersma, Sophie Garnier, Garðar Sveinbjörnsson, W. M. Monique Verschuuren, Michael Lee, Nilesh J. Samani, Yifan Yang, Harry Hemingway, David J. Carey, Sundarajan Srinivasan, James P. Cook, Marion van Vugt, Andrew P. Morris, Tõnu Esko, Mari‐Liis Tammesoo, Unnur Thorsteinsdottir, Abirami Veluchamy, John Baksi, Isabelle Bond
article en
48 citations

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.

Nature GeneticsVol. 56(12)
Statens Serum Institut (DK), Broad Institute (US), Boston University (US), Dalarna University (SE), Uppsala University (SE), University of Copenhagen (DK), Geisinger Medical Center (US), St Bartholomew's Hospital (GB), deCODE Genetics (Iceland) (IS), University Medical Center Groningen (NL), Centre for Human Genetics (GB), University of Nottingham (GB), University of Liverpool (GB), Université de Bordeaux (FR), University of Leicester (GB), Inserm (FR), University of Iceland (IS), University of Groningen (NL), University of Dundee (GB), Regeneron (United States) (US), Lund University (SE), Guy's and St Thomas' NHS Foundation Trust (GB), Vanderbilt University (US), Aarhus University (DK), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Royal Brompton & Harefield NHS Foundation Trust (GB), Montreal Heart Institute (CA), Sahlgrenska University Hospital (SE), Novo Nordisk Foundation (DK), Erasmus MC (NL), Glenfield Hospital (GB), Fondation Jean Dausset-CEPH (FR), Aarhus University Hospital (DK), Ninewells Hospital (GB), Copenhagen University Hospital (DK), Rigshospitalet (DK), Harefield Hospital (GB), Karolinska Institutet (SE), University of Manchester (GB), University Medical Center Utrecht (NL), British Heart Foundation (GB), National Institute for Health and Care Research (GB), Sorbonne Université (FR), University of Oxford (GB), Centre National de Recherche en Génomique Humaine (FR), Massachusetts General Hospital (US), Clinical Research Institute (US), Assistance Publique – Hôpitaux de Paris (FR), Lung Institute (US), National Institute for Public Health and the Environment (NL), Bordeaux Population Health (FR), National Heart, Lung, and Blood Institute (US), Arthritis UK (GB), Pitié-Salpêtrière Hospital (FR), Framingham Heart Study (US), Duke Medical Center (US), CEA Paris-Saclay (FR), Boston Public Schools (US), Skåne University Hospital (SE), Health Data Research UK (GB), Genomics (United Kingdom) (GB), Amsterdam University Medical Centers (NL), Zealand University Hospital Køge (DK), Génétique Médicale & Génomique Fonctionelle (FR), MRC London Institute of Medical Sciences (GB), NIHR Leicester Biomedical Research Centre (GB), Biologie des maladies cardiovasculaires, University College London (GB), Imperial College London (GB), Geisinger Health System (US), University of Tartu (EE), Université de Montréal (CA), University of Pennsylvania (US), National University of Malaysia (MY), Vanderbilt University Medical Center (US), University of Edinburgh (GB)
Israel Cancer Research Fund, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Imperial College London, University College London, Rosetrees Trust, Medical Research Council
Good health and well-being
Openalex Percentile: Top 1%
RNA modifications and cancer
11.22
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