Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.
Zheng SL., Henry A., Cannie D., Lee M., Miller D., McGurk KA., Bond I., Xu X., Issa H., Francis C., De Marvao A., Theotokis PI., Buchan RJ., Speed D., Abner E., Adams L., Aragam KG., Ärnlöv J., Raja AA., Backman JD., Baksi J., Barton PJR., Biddinger KJ., Boersma E., Brandimarto J., Brunak S., Bundgaard H., Carey DJ., Charron P., Cook JP., Cook SA., Denaxas S., Deleuze J-F., Doney AS., Elliott P., Erikstrup C., Esko T., Farber-Eger EH., Finan C., Garnier S., Ghouse J., Giedraitis V., Guðbjartsson DF., Haggerty CM., Halliday BP., Helgadottir A., Hemingway H., Hillege HL., Kardys I., Lind L., Lindgren CM., Lowery BD., Manisty C., Margulies KB., Moon JC., Mordi IR., Morley MP., Morris AD., Morris AP., Morton L., Noursadeghi M., Ostrowski SR., Owens AT., Palmer CNA., Pantazis A., Pedersen OBV., Prasad SK., Shekhar A., Smelser DT., Srinivasan S., Stefansson K., Sveinbjörnsson G., Syrris P., Tammesoo M-L., Tayal U., Teder-Laving M., Thorgeirsson G., Thorsteinsdottir U., Tragante V., Trégouët D-A., Treibel TA., Ullum H., Valdes AM., van Setten J., van Vugt M., Veluchamy A., Verschuren WMM., Villard E., Yang Y., COVIDsortium None., DBDS Genomic Consortium None., Estonian Biobank Research Team None., HERMES Consortium None., Asselbergs FW., Cappola TP., Dube M-P., Dunn ME., Ellinor PT., Hingorani AD., Lang CC., Samani NJ., Shah SH., Smith JG., Vasan RS., O'Regan DP., Holm H., Noseda M., Wells Q., Ware JS., Lumbers RT.
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.