Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience.

Autor:	Jurgens SJ; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Rämö JT; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland., Kramarenko DR; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; European Reference Network for rare low prevalence and complex diseases of the heart: ERN GUARD-Heart, Amsterdam, the Netherlands., Wijdeveld LFJM; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Physiology, Amsterdam UMC location, Vrije Universiteit, Amsterdam, the Netherlands., Haas J; Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, Heidelberg, Germany.; Site Heidelberg/Mannheim, DZHK, Heidelberg, Germany., Chaffin MD; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Garnier S; Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics and Pathophysiology of Cardiovascular Disease, Sorbone Université, INSERM, Paris, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris, France., Gaziano L; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Weng LC; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Lipov A; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Zheng SL; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, Imperial College London, London, UK.; Royal Brompton and Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Henry A; Institute of Cardiovascular Science, University College London, London, UK.; Institute of Health Informatics, University College London, London, UK., Huffman JE; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.; Palo Alto Veterans Institute for Research (PAVIR), Palo Alto Health Care System, Palo Alto, CA, USA.; Harvard Medical School, Boston, MA, USA., Challa S; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rühle F; Bioinformatics Core Facility, Institute of Molecular Biology gGmbH (IMB), Mainz, Germany.; Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany., Verdugo CD; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Krijger Juárez C; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Kany S; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., van Orsouw CA; Department of Clinical Genetics, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Biddinger K; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Poel E; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Elliott AL; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.; Harvard Medical School, Boston, MA, USA.; Department of Psychiatry and Center for Genomic Medicine, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Wang X; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Francis C; National Heart and Lung Institute, Imperial College London, London, UK.; Royal Brompton and Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Ruan R; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Koyama S; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Beekman L; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Zimmerman DS; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Deleuze JF; CEA, Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, Evry, France.; Laboratory of Excellence in Medical Genomics, GENMED, Evry, France.; Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France., Villard E; Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics and Pathophysiology of Cardiovascular Disease, Sorbone Université, INSERM, Paris, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris, France., Trégouët DA; Laboratory of Excellence in Medical Genomics, GENMED, Evry, France.; Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, INSERM, Bordeaux, France., Isnard R; Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics and Pathophysiology of Cardiovascular Disease, Sorbone Université, INSERM, Paris, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.; APHP, Cardiology and Genetics Departments, Pitié-Salpêtrière Hospital, Paris, France., Boomsma DI; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., de Geus EJC; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.; Amsterdam Public Health Research Institute, Amsterdam UMC location, Vrije Universiteit, Amsterdam, the Netherlands., Tadros R; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; Cardiovascular Genetics Centre, Montreal Heart Institute, Montreal, QC, Canada.; Faculty of Medicine, Université de Montréal, Montreal, QC, Canada., Pinto YM; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; European Reference Network for rare low prevalence and complex diseases of the heart: ERN GUARD-Heart, Amsterdam, the Netherlands.; Department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Wilde AAM; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; European Reference Network for rare low prevalence and complex diseases of the heart: ERN GUARD-Heart, Amsterdam, the Netherlands.; Department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Hottenga JJ; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.; The Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Sinisalo J; Department of Cardiology, Helsinki University Hospital, Helsinki, Finland.; Heart and Lung Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland., Niiranen T; Department of Internal Medicine, University of Turku, Helsinki, Finland.; Division of Medicine, Turku University Hospital, Helsinki, Finland.; Finnish Institute for Health and Welfare (THL), Helsinki, Finland., Walsh R; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Schmidt AF; Department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.; University College London British Heart Foundation Research Accelerator, London, UK.; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Choi SH; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biostatistics, Boston University, Boston, MA, USA., Chang KM; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Tsao PS; Palo Alto Health Care System, Palo Alto, CA, USA.; Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Matthews PM; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, Imperial College London, London, UK., Ware JS; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, Imperial College London, London, UK.; Royal Brompton and Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Lumbers RT; Institute of Health Informatics, University College London, London, UK.; The National Institute for Health Research, University College London Hospitals Biomedical Research Centre, University College London, London, UK., van der Crabben S; Department of Clinical Genetics, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Laukkanen J; Department of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.; Central Finland Biobank, Central Finland Health Care District, Jyväskylä, Finland., Palotie A; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Amin AS; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.; European Reference Network for rare low prevalence and complex diseases of the heart: ERN GUARD-Heart, Amsterdam, the Netherlands.; Department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands., Charron P; Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics and Pathophysiology of Cardiovascular Disease, Sorbone Université, INSERM, Paris, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.; APHP, Cardiology and Genetics Departments, Pitié-Salpêtrière Hospital, Paris, France., Meder B; Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, Heidelberg, Germany.; Site Heidelberg/Mannheim, DZHK, Heidelberg, Germany., Ellinor PT; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu., Daly M; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland. mark.daly@helsinki.fi.; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. mark.daly@helsinki.fi.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. mark.daly@helsinki.fi., Aragam KG; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. karagam@broadinstitute.org.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. karagam@broadinstitute.org., Bezzina CR; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands. c.r.bezzina@amsterdamumc.nl.; European Reference Network for rare low prevalence and complex diseases of the heart: ERN GUARD-Heart, Amsterdam, the Netherlands. c.r.bezzina@amsterdamumc.nl.
Jazyk:	angličtina
Zdroj:	Nature genetics [Nat Genet] 2024 Dec; Vol. 56 (12), pp. 2636-2645. Date of Electronic Publication: 2024 Nov 21.
DOI:	10.1038/s41588-024-01975-5
Abstrakt:	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. Competing Interests: Competing interests: P.T.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb and Pfizer; he has consulted for Bayer AG, Novartis and MyoKardia. K.G.A. has received sponsored research support from Sarepta Therapeutics and Bayer AG, and reports a research collaboration with Novartis. Y.M.P. is involved in the development of therapies for DCM as an advisor to Forbion and Medical Director at ARMGO pharma and CMO at Phlox Therapeutics. P.C. reports personal fees for consultancies, outside the present work, for Amicus, OWKIN, Pfizer and SANOFI. J.S.W. has received research support from Bristol Myers Squibb, and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen and Tenaya Therapeutics. The remaining authors declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
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