Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
Year: 2024
Type: article
Study design: Observational Study
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.
Source: Nature Genetics
Authors: Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, David Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Xu, Hanane Issa, Catherine Francis, Antonio De Marvao, Pantazis I. Theotokis, Rachel J. Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua D. Backman, John Baksi, Paul J. R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean-François Deleuze, Alexander S. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daniel F. Guðbjartsson, Christopher M. Haggerty, Brian P. Halliday, Anna Helgadottir, Harry Hemingway, Hans L. Hillege, Isabella Kardys, Lars Lind, Cecilia M. Lindgren, Brandon D. Lowery, Charlotte Manisty, Kenneth B. Margulies, James C. Moon, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Lori Morton, Mahdad Noursadeghi, Sisse R. Ostrowski, Anjali T. Owens, Colin N. A. Palmer, Antonis Pantazis, Ole B. V. Pedersen, Sanjay K. Prasad, Akshay Shekhar, Diane T. Smelser, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Petros Syrris, Mari-Liis Tammesoo, Upasana Tayal, Maris Teder-Laving, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Vinicius Tragante, David-Alexandre Trégouët, Thomas A. Treibel, Henrik Ullum, Ana M. Valdes, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuren, Eric Villard, Yifan Yang, COVIDsortium, Mahdad Noursadeghi, Ole B. V. Pedersen, Kari Stefansson, Unnur Thorsteinsdottir, Henrik Ullum, Folkert W. Asselbergs, Antonio De Marvao, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Sophie Garnier, Chim C. Lang, Andrew P. Morris, Lori Morton, Colin N. A. Palmer, Nilesh J. Samani, Svati H. Shah, Akshay Shekhar, J. Gustav Smith, Sundarajan Srinivasan, Guðmundur Thorgeirsson, Ramachandran S. Vasan, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuuren, Eric Villard, Quinn Wells, Folkert W. Asselbergs, Thomas P. Cappola, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Aroon D. Hingorani, Chim C. Lang, Nilesh J. Samani, Svati H. Shah, J. Gustav Smith, Ramachandran S. Vasan, Declan P. O’Regan, Hilma Holm, Michela Noseda, Quinn Wells, James S. Ware, R. Thomas Lumbers
Institutions: Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, MRC London Institute of Medical Sciences, Imperial College London, Medical Research Council, University College London, St Bartholomew's Hospital, Broad Institute, Aarhus University, University of Tartu, Geisinger Health System, Massachusetts General Hospital, Dalarna University, Karolinska Institutet, Copenhagen University Hospital, Rigshospitalet, Regeneron (United States), Erasmus MC Hart en Vaat Instituut, University of Pennsylvania, University of Copenhagen, Novo Nordisk Foundation, Geisinger Medical Center, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Fondation pour l’innovation en Cadiométabolisme et Nutrition, University of Liverpool, National Institute for Health and Care Research, UCL Biomedical Research Centre, Health Data Research UK, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Fondation Jean Dausset-CEPH, Centre National de Recherche en Génomique Humaine, Institut de biologie François Jacob, University of Dundee, Ninewells Hospital, Aarhus University Hospital, Vanderbilt University Medical Center, Uppsala University, deCODE Genetics (Iceland), University of Iceland, University Medical Center Groningen, University of Groningen, Centre for Human Genetics, University of Oxford, University of Manchester, University of Edinburgh, Zealand University Hospital Køge, Université de Bordeaux, Inserm, Bordeaux Population Health, Statens Serum Institut, University of Nottingham, University Medical Center Utrecht, National Institute for Public Health and the Environment, Montreal Heart Institute, Amsterdam University Medical Centers, Université de Montréal, National University of Malaysia, University of Leicester, Glenfield Hospital, NIHR Leicester Biomedical Research Centre, Duke University, Lund University, Duke Medical Center, Skåne University Hospital, Duke Clinical Research Institute, Sahlgrenska University Hospital, University of Gothenburg, Boston University, Framingham Heart Study, Vanderbilt University, British Heart Foundation
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: 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, Novo Nordisk Fonden, Medical Research Council
Awards: G1138586538, Genetic determinants of aortic morphology and function, G1452829347, Research Excellence (round 3), G1828712186, Spatially resolved cellular and molecular drivers of cardiac remodelling in healthy and failing human hearts (joint funding with DZHK), intake 2018 – PhD Studentship Ms Vanessa Acquaah; Mr Albert Henry; Rashbrook; Mr Benjamin Ringham-Terry, Rare variant and phenotype analyses of adult cardiac trabecular morphology in the UK Biobank, Curing genetic heart muscle disease (CureHeart), Human Immune Response Variation in Tuberulosis, G402563391, Machine learning to model disease mechanisms and predict outcomes in cardiomyopathy, G5204603102, G534532664, G5562295050, Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification., G6119950516, Defining the genetics, biomarkers and outcomes for dilated cardiomyopathy: a prospective multi- centre study (GO-DCM), G6868616705, Improving prevention and treatment of heart failure in type 1 diabetes, G7227888905, G780909024, Examining the role of mitochondrial oxidative stress in dilated cardiomyopathy using a novel therapeutic probe, G8685575625, Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification.
OpenAlex ID: W4404595279