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Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Zheng SL 1 , Henry A 2 , Cannie D 2 , Lee M 1 , Miller D 3 , McGurk KA 1 Show all authors , Bond I 2 , Xu X 1 , Issa H 4 , Francis C 1 , De Marvao A 1 , Theotokis PI 1 , Buchan RJ 1 , Speed D 5 , Abner E 6 , Adams L 7 , Aragam KG 8 , Ärnlöv J 9 , Raja AA 10 , Backman JD 11 , Baksi J 12 , Barton PJR 1 , Biddinger KJ 8 , Boersma E 13 , Brandimarto J 14 , Brunak S 15 , Bundgaard H 10 , Carey DJ 16 , Charron P 17 , Cook JP 18 , Cook SA 1 , Denaxas S 4 , Deleuze JF 19 , Doney AS 20 , Elliott P 2 , Erikstrup C 21 , Esko T 6 , Farber-Eger EH 22 , Finan C 2 , Garnier S 17 , Ghouse J 10 , Giedraitis V 23 , Guðbjartsson DF 24 , Haggerty CM 16 , Halliday BP 1 , Helgadottir A 24 , Hemingway H 4 , Hillege HL 25 , Kardys I 13 , Lind L 26 , Lindgren CM 27 , Lowery BD 22 , Manisty C 2 , Margulies KB 15 , Moon JC 2 , Mordi IR 20 , Morley MP 15 , Morris AD 28 , Morris AP 29 , Morton L 30 , Noursadeghi M 31 , Ostrowski SR 32 , Owens AT 14 , Palmer CNA 33 , Pantazis A 12 , Pedersen OBV 34 , Prasad SK 1 , Shekhar A 30 , Smelser DT 16 , Srinivasan S 33 , Stefansson K 24 , Sveinbjörnsson G 24 , Syrris P 2 , Tammesoo ML 6 , Tayal U 1 , Teder-Laving M 6 , Thorgeirsson G 24 , Thorsteinsdottir U 24 , Tragante V 24 , Trégouët DA 35 , Treibel TA 2 , Ullum H 36 , Valdes AM 37 , van Setten J 38 , van Vugt M 38 , Veluchamy A 33 , Verschuren WMM 39 , Villard E 17 , Yang Y 14 , COVIDsortium , DBDS Genomic Consortium , Estonian Biobank Research Team , HERMES Consortium , Asselbergs FW 2 , Cappola TP 14 , Dube MP 40 , Dunn ME 30 , Ellinor PT 27 , Hingorani AD 2 , Lang CC 20 , Samani NJ 41 , Shah SH 42 , Smith JG 43 , Vasan RS 44 , O'Regan DP 45 , Holm H 24 , Noseda M 1 , Wells Q 46 , Ware JS 47 , Lumbers RT 48

Affiliations 

  • 1 National Heart and Lung Institute, Imperial College London, London, UK
  • 2 Institute of Cardiovascular Science, University College London, London, UK
  • 3 Division of Biosciences, University College London, London, UK
  • 4 Institute of Health Informatics, University College London, London, UK
  • 5 Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark
  • 6 Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
  • 7 Geisinger Health System, Danville, PA, USA
  • 8 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
  • 9 Department of Neurobiology, Care Sciences and Society/Section of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden
  • 10 Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  • 11 Analytical Genetics, Regeneron Genetics Center, Tarrytown, NY, USA
  • 12 Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
  • 13 Erasmus MC, Cardiovascular Institute, Thorax Center, Department of Cardiology, Utrecht, the Netherlands
  • 14 Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • 15 Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 16 Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA
  • 17 Sorbonne Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, ICAN Institute for Cardiometabolism and Nutrition, Paris, France
  • 18 Department of Biostatistics, University of Liverpool, Liverpool, UK
  • 19 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France
  • 20 Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
  • 21 Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
  • 22 Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
  • 23 Department of Public Health and Caring Sciences, Geriatrics, Uppsala, Sweden
  • 24 deCODE genetics/Amgen Inc., Reykjavik, Iceland
  • 25 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • 26 Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • 27 Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • 28 Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
  • 29 Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
  • 30 Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA
  • 31 Research Department of Infection, Division of Infection and Immunity, University College London, London, UK
  • 32 Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  • 33 Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
  • 34 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen University Hospital, Copenhagen, Denmark
  • 35 Laboratory of Excellence GENMED (Medical Genomics), Paris, France
  • 36 Statens Serum Institut, Copenhagen, Denmark
  • 37 Injury, Recovery and Inflammation Sciences, School of Medicine, University of Nottingham, Nottingham, UK
  • 38 Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
  • 39 Department Life Course, Lifestyle and Health, Centre for Prevention, Lifestyle and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
  • 40 Montreal Heart Institute, Montreal Heart Institute, Montreal, Quebec, Canada
  • 41 Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
  • 42 Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, USA
  • 43 Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
  • 44 National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA
  • 45 MRC Laboratory of Medical Sciences, London, UK
  • 46 Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA
  • 47 National Heart and Lung Institute, Imperial College London, London, UK. j.ware@imperial.ac.uk
  • 48 Institute of Health Informatics, University College London, London, UK. t.lumbers@ucl.ac.uk
Nat Genet, 2024 Dec;56(12):2646-2658.
PMID: 39572783 DOI: 10.1038/s41588-024-01952-y

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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