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

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.

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Publication Details

Journal
Nature Genetics
Published
2024-11-21
DOI
https://doi.org/10.1038/s41588-024-01975-5
Citations
43
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
23.66

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article

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

Dominic S. Zimmerman, Albert Henry, Saketh Challa, Alex Lipov et al.
43 citations
Nature Genetics
Genetic Associations and Epidemiology
23.66
article

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

Dominic S. Zimmerman, Albert Henry, Saketh Challa, Alex Lipov, Lu‐Chen Weng, Christian Krijger Juárez, Satoshi Koyama, Liam Gaziano, Jennifer E. Huffman, Richard Isnard, Philippe Charron, Connie R. Bezzina, Jan Haas, Leonoor F. J. M. Wijdeveld, Amand F. Schmidt, Daria R. Kramarenko, James S. Ware, Shinwan Kany, Leander Beekman, Rafik Tadros, Jouke‐Jan Hottenga, Catherine Francis, Sean L. Zheng, Frank Rühle, Benjamin Meder, Carmen Diaz Verdugo, Edwin Poel, Kyong‐Mi Chang, Eric Villard, Seung Hoan Choi, Krishna G. Aragam, Richard Ruan, Joel Rämö, Ahmad S. Amin, Roddy Walsh, Jari A. Laukkanen, Philip S. Tsao, Juha P. Sinisalo, Yigal M. Pinto, Mark D. Chaffin, Patrick T. Ellinor, Paul M. Matthews, David‐Alexandre Trégouët, Eco J. C. de Geus, Teemu Niiranen, Sean J. Jurgens, R Thomas Lumbers, Aarno V. Palotie, Kiran J. Biddinger, Sophie Garnier, Xin Wang, Amanda L. Elliott, Mark J. Daly, Jean‐François Deleuze, D.I. Boomsma, Arthur A.M. Wilde, Saskia van der Crabben, Constance A. van Orsouw
article en
43 citations

Abstract

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.

Nature GeneticsVol. 56(12)
Broad Institute (US), Boston University (US), University of Helsinki (FI), Harvard University (US), Université de Bordeaux (FR), Inserm (FR), University of Turku (FI), Universität Hamburg (DE), University of Eastern Finland (FI), Utrecht University (NL), Guy's and St Thomas' NHS Foundation Trust (GB), VA Palo Alto Health Care System (US), Heidelberg University (DE), University of Münster (DE), Cardiovascular Institute of the South (US), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Montreal Heart Institute (CA), Helsinki University Hospital (FI), VA Boston Healthcare System (US), Turku University Hospital (FI), University Hospital Heidelberg (DE), Fondation Jean Dausset-CEPH (FR), Harefield Hospital (GB), University Medical Center Utrecht (NL), British Heart Foundation (GB), National Institute for Health and Care Research (GB), Finnish Institute for Health and Welfare (FI), Sorbonne Université (FR), Centre National de Recherche en Génomique Humaine (FR), Massachusetts General Hospital (US), Palo Alto Veterans Institute for Research (US), Assistance Publique – Hôpitaux de Paris (FR), Bordeaux Population Health (FR), Amsterdam Neuroscience (NL), University Medical Center Hamburg-Eppendorf (DE), Pitié-Salpêtrière Hospital (FR), CEA Paris-Saclay (FR), Philadelphia VA Medical Center (US), Institute for Molecular Medicine Finland (FI), Central Finland Health Care District (FI), ERN GUARD-Heart (NL), Unité de recherche sur les maladies cardiovasculaires et métaboliques (FR), Amsterdam University Medical Centers (NL), Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR), MRC London Institute of Medical Sciences (GB), Institute of Molecular Biology (DE), University College London (GB), Imperial College London (GB), Université de Montréal (CA), University of Pennsylvania (US), Vrije Universiteit Amsterdam (NL), University of Amsterdam (NL), Stanford University (US)
American Heart Association, Aarne Koskelon Säätiö, Amsterdam University Medical Centers, European Commission, Deutsche Forschungsgemeinschaft, Associação Fundo de Incentivo à Pesquisa, National Institutes of Health, HORIZON EUROPE European Innovation Council
Good health and well-being
Openalex Percentile: Top 0%
Genetic Associations and Epidemiology
23.66
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