Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
| Title: | 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.; Lind, Lars; Ostrowski, Sisse R.; Pedersen, Ole B.V.; Ullum, Henrik |
| Source: | Zheng , S L , Henry , A , Cannie , D , Lee , M , Miller , D , McGurk , K A , Bond , I , Xu , X , Issa , H , Francis , C , De Marvao , A , Theotokis , P I , Buchan , R J , Speed , D , Abner , E , Adams , L , Aragam , K G , Ärnlöv , J , Raja , A A , Backman , J D , Baksi , J , Barton , P J R , Biddinger , K J , Boersma , E , Brandimarto , J , Brunak , S , Bundgaard , H , Carey , D J , Charron , P , Cook , J P , Cook , S A , Denaxas , S , Deleuze , J F , Doney , A S , Elliott , P , Erikstrup , C , Esko , T , Farber-Eger , E H , Finan , C , Garnier , S , Ghouse , J , Giedraitis , V , Guðbjartsson , D F , Haggerty , C M , Halliday , B P , Lind , L , Ostrowski , S R , Pedersen , O B V , Ullum , H , Pedersen , O B V , COVIDsortium , DBDS Genomic Consortium , Estonian Biobank Research Team & HERMES Consortium 2024 , ' Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy ' , Nature Genetics , vol. 56 , no. 12 , pp. 2646–2658 . |
| Publisher Information: | 2024 |
| Document Type: | Electronic Resource |
| 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.; 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. |
| Index Terms: | article |
| URL: | https://researchprofiles.ku.dk/da/publications/e8bdb13f-6958-418c-bf8a-f2581d78a993; https://doi.org/10.1038/s41588-024-01952-y; https://curis.ku.dk/ws/files/426176766/s41588_024_01952_y.pdf |
| Availability: | Open access content. Open access content; info:eu-repo/semantics/openAccess |
| Note: | application/pdf; English |
| Other Numbers: | DAV oai:pure.atira.dk:publications/e8bdb13f-6958-418c-bf8a-f2581d78a993; 1579436740 |
| Contributing Source: | UNIV OF COPENHAGEN; From OAIster®, provided by the OCLC Cooperative. |
| Accession Number: | edsoai.on1579436740 |
| Database: | OAIster |