Genome-wide association analysis reveals insights into the molecular etiology underlying 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 , Axelsson Raja Anna , Backman Joshua D , Baksi John , Barton Paul JR , Biddinger Kiran J , Boersma Eric , Brandimarto Jeffrey , Brunak Søren , Brundgaard 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 , 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 NA , Pantazis Antonis , Pedersen Ole BV , Prasad Sanjay K , Shekhar Akshay , Smelser Diane T , Srinivasan Sundarajan , 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 , Verschuuren W.M.Monique , Villard Eric , Yang Yifan ,   COVIDsortium,   DBDS Genomic Consortium,   Genomics England Research Consortium,   HERMES Consortium, 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: September 2023

Dilated cardiomyopathy (DCM) is a clinical disorder characterised by reduced contractility of the heart muscle that is not explained by coronary artery disease or abnormal haemodynamic loading. Although Mendelian disease is well described, clinical testing yields a genetic cause in a minority of patients. The role of complex inheritance is emerging, however the common genetic architecture is relatively unexplored. To improve our understanding of the genetic basis of DCM, we perform a genome-wide association study (GWAS) meta-analysis comprising 14,255 DCM cases and 1,199,156 controls, and a multi-trait GWAS incorporating correlated cardiac magnetic resonance imaging traits of 36,203 participants. We identify 80 genetic susceptibility loci and prioritize 61 putative effector genes for DCM by synthesizing evidence from 8 gene prioritization strategies. Rare variant association testing identifies genes associated with DCM, includingMAP3K7, NEDD4L, andSSPN. Through integration with single-nuclei transcriptomics from 52 end-stage DCM patients and 18 controls, we identify cellular states, biological pathways, and intercellular communications driving DCM pathogenesis. Finally, we demonstrate that a polygenic score predicts DCM in the general population and modulates the penetrance of rare pathogenic and likely pathogenic variants in DCM-causing genes. Our findings may inform the design of novel clinical genetic testing strategies incorporating polygenic background and the genes and pathways identified may inform the development of targeted therapeutics.