Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
Authors: Zheng Sean L. , Henry Albert , Cannie Douglas , Lee Michael , Miller David , McGurk Kathryn A. , Bond Isabelle , Xu Xiao , Issa Hanane , Francis Catherine , De Marvao Antonio , Theotokis Pantazis I. , Buchan Rachel J. , Speed Doug , Abner Erik , Adams Lance , Aragam Krishna G. , Ärnlöv Johan , Raja Anna Axelsson , Backman Joshua D. , Baksi John , Barton Paul J. R. , Biddinger Kiran J. , Boersma Eric , Brandimarto Jeffrey , Brunak Søren , Bundgaard Henning , Carey David J. , Charron Philippe , Cook James P. , Cook Stuart A. , Denaxas Spiros , Deleuze Jean-François , Doney Alexander S. , Elliott Perry , Erikstrup Christian , Esko Tõnu , Farber-Eger Eric H. , Finan Chris , Garnier Sophie , Ghouse Jonas , Giedraitis Vilmantas , Guðbjartsson Daniel F. , Haggerty Christopher M. , Halliday Brian P. , Helgadottir Anna , Hemingway Harry , Hillege Hans L. , Kardys Isabella , Lind Lars , Lindgren Cecilia M. , Lowery Brandon D. , Manisty Charlotte , Margulies Kenneth B. , Moon James C. , Mordi Ify R. , Morley Michael P. , Morris Andrew D. , Morris Andrew P. , Morton Lori , Noursadeghi Mahdad , Ostrowski Sisse R. , Owens Anjali T. , Palmer Colin N. A. , Pantazis Antonis , Pedersen Ole B. V. , Prasad Sanjay K. , Shekhar Akshay , Smelser Diane T. , Srinivasan Sundararajan , Stefansson Kari , Sveinbjörnsson Garðar , Syrris Petros , Tammesoo Mari-Liis , Tayal Upasana , Teder-Laving Maris , Thorgeirsson Guðmundur , Thorsteinsdottir Unnur , Tragante Vinicius , Trégouët David-Alexandre , Treibel Thomas A. , Ullum Henrik , Valdes Ana M. , van Setten Jessica , van Vugt Marion , Veluchamy Abirami , Verschuren W. M. Monique , Villard Eric , Yang Yifan ,   COVIDsortium, Noursadeghi Mahdad ,   DBDS Genomic Consortium, Pedersen Ole B. V. , Stefansson Kari , Thorsteinsdottir Unnur , Ullum Henrik ,   Estonian Biobank Research Team,   HERMES Consortium, Asselbergs Folkert W. , De Marvao Antonio , Dube Marie-Pierre , Dunn Michael E. , Ellinor Patrick T. , Garnier Sophie , Lang Chim C. , Morris Andrew P. , Morton Lori , Palmer Colin N. A. , Samani Nilesh J. , Shah Svati H. , Shekhar Akshay , Smith J. Gustav , Srinivasan Sundarajan , Thorgeirsson Guðmundur , Vasan Ramachandran S. , van Setten Jessica , van Vugt Marion , Veluchamy Abirami , Verschuuren W. M. Monique , Villard Eric , Wells Quinn , Asselbergs Folkert W. , Cappola Thomas P. , Dube Marie-Pierre , Dunn Michael E. , Ellinor Patrick T. , Hingorani Aroon D. , Lang Chim C. , Samani Nilesh J. , Shah Svati H. , Smith J. Gustav , Vasan Ramachandran S. , O’Regan Declan P. , Holm Hilma , Noseda Michela , Wells Quinn , Ware James S. , Lumbers R. Thomas 
Published: November 2024

AbstractDilated 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.