Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience
: Jurgens, Sean J.; Rämö, Joel T.; Kramarenko, Daria R.; Wijdeveld, Leonoor F. J. M.; Haas, Jan; Chaffin, Mark D.; Garnier, Sophie; Gaziano, Liam; Weng, Lu-Chen; Lipov, Alex; Zheng, Sean L.; Henry, Albert; Huffman, Jennifer E.; Challa, Saketh; Rühle, Frank; Verdugo, Carmen Diaz; Krijger Juárez, Christian; Kany, Shinwan; van Orsouw, Constance A.; Biddinger, Kiran; Poel, Edwin; Elliott, Amanda L.; Wang, Xin; Francis, Catherine; Ruan, Richard; Koyama, Satoshi; Beekman, Leander; Zimmerman, Dominic S.; Deleuze, Jean-François; Villard, Eric; Trégouët, David-Alexandre; Isnard, Richard; ; FinnGen; VA Million Veteran Program; HERMES Consortium; Boomsma, Dorret I.; de Geus, Eco J. C.; Tadros, Rafik; Pinto, Yigal M.; Wilde, Arthur A. M.; Hottenga, Jouke-Jan; Sinisalo, Juha; Niiranen, Teemu; Walsh, Roddy; Schmidt, Amand F.; Choi, Seung Hoan; Chang, Kyong-Mi; Tsao, Philip S.; Matthews, Paul M.; Ware, James S.; Lumbers, R. Thomas; van der Crabben, Saskia; Laukkanen, Jari; Palotie, Aarno; Amin, Ahmad S.; Charron, Philippe; Meder, Benjamin; Ellinor, Patrick T.; Daly, Mark; Aragam, Krishna G.; Bezzina, Connie R.
Publisher: NATURE PORTFOLIO
: BERLIN
: 2024
: Nature Genetics
: NATURE GENETICS
: NAT GENET
: 56
: 12
: 2636
: 2645
: 30
: 1061-4036
: 1546-1718
DOI: https://doi.org/10.1038/s41588-024-01975-5
: https://www.nature.com/articles/s41588-024-01975-5
: https://research.utu.fi/converis/portal/detail/Publication/477060075
Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.Genome-wide association and multitrait analyses for dilated cardiomyopathy (DCM) using 9,365 cases and 946,368 controls provide insights into the mechanisms underlying DCM and myocardial resilience
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We gratefully thank all research participants, as this work would not have been possible without their contributions. Relevant funding sources for the FinnGen, UKB and All of Us datasets are presented in the Supplementary Note. S.J.J. received research support through the Junior Clinical Scientist Fellowship from the Dutch Heart Foundation (03-007-2022-0035), as well as a doctoral fellowship from the Amsterdam UMC. J.T.R. was supported by a research grant from the Aarne Koskelo Foundation. S.K. was supported by the Walter Benjamin Fellowship from the Deutsche Forschungsgemeinschaft (521832260). L.F.J.M.W. was supported by the Amsterdam UMC YTF, Dutch Heart Foundation Student Grant and the AFIP foundation. P.T.E. was supported by funding from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 5R01HL139731), by a grant from the American Heart Association (18SFRN34110082) and from the European Union (MAESTRIA 965286). This work was further supported by a grant from the National Institutes of Health (1K08HL153937) and a grant from the American Heart Association (862032) to K.G.A. C.R.B. was supported by funding from the Dutch Heart Foundation (CVON 2018-30 PREDICT2) and the Pathfinder Cardiogenomics programme of the European Innovation Council of the European Union (DCM-NEXT). A.A.M., D.R.K. and Y.M.P. were supported by funding from the PSIDER programme of the Netherlands Organisation for Health Research and Development (ZonMW; project 40-46800-98-018). T.N. was supported by grants from the Sigrid Jusélius Foundation, the Finnish Foundation for Cardiovascular Research and the Finnish Research Council (grants 321351 and 354447). This work was supported by a grant from the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013)—a research program managed by the National Research Agency (ANR) as part of the French Investment for the Future; Aviesan-ITMO Genetique-Genomique-Bioinformatique (ResDiCard: Resolving diagnostic deadlock in cardiomyopathies) and the Société Française de Cardiologie/Fédération Française de Cardiologie; the SFB-TR19 registry was supported by the Deutsche Forschungsgemeinschaft (DFG). The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403); the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; and grants from the German Center for Cardiovascular Research (DZHK). The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported at the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. D.A.T. is supported by the ‘EPIDEMIOM-VTE’ Senior Chair from the Initiative of Excellence of the University of Bordeaux. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award I01-BX003362 to P.T. and K.-M.C. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. This work was also supported by the Sir Jules Thorn Charitable Trust (21JTA), Medical Research Council (UK), British Heart Foundation (RE/18/4/34215, SP/17/11/32885), the NIHR Imperial College Biomedical Research Centre, Pathfinder Cardiogenomics programme of the European Innovation Council of the European Union (DCM-NEXT) (101115416) to J.S.W.
