Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
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, 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
Journal: Nature Genetics (2024)

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.