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

Autor:	Zheng SL; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Royal Brompton & 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., Cannie D; Institute of Cardiovascular Science, University College London, London, UK.; Barts Heart Centre, St Bartholomew's Hospital, London, UK., Lee M; National Heart and Lung Institute, Imperial College London, London, UK., Miller D; Division of Biosciences, University College London, London, UK., McGurk KA; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bond I; Institute of Cardiovascular Science, University College London, London, UK., Xu X; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK., Issa H; Institute of Health Informatics, University College London, London, UK., Francis C; National Heart and Lung Institute, Imperial College London, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., De Marvao A; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Theotokis PI; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Buchan RJ; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Speed D; Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark., Abner E; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Adams L; Geisinger Health System, Danville, PA, USA., Aragam KG; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ärnlöv J; Department of Neurobiology, Care Sciences and Society/Section of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.; School of Health and Social Sciences, Dalarna University, Falun, Sweden., Raja AA; Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Backman JD; Analytical Genetics, Regeneron Genetics Center, Tarrytown, NY, USA., Baksi J; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Barton PJR; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Biddinger KJ; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Boersma E; Erasmus MC, Cardiovascular Institute, Thorax Center, Department of Cardiology, Utrecht, the Netherlands., Brandimarto J; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Brunak S; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Bundgaard H; Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Carey DJ; Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA., Charron P; Sorbonne Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, ICAN Institute for Cardiometabolism and Nutrition, Paris, France.; APHP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France., Cook JP; Department of Biostatistics, University of Liverpool, Liverpool, UK., Cook SA; National Heart and Lung Institute, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Denaxas S; Institute of Health Informatics, University College London, London, UK.; Health Data Research UK, University College London, London, UK.; British Heart Foundation Data Science Centre, London, UK.; The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK., Deleuze JF; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France.; Laboratory of Excellence GENMED (Medical Genomics), Paris, France.; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France., Doney AS; Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK., Elliott P; Institute of Cardiovascular Science, University College London, London, UK.; Barts Heart Centre, St Bartholomew's Hospital, London, UK., Erikstrup C; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.; Deparment of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark., Esko T; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Farber-Eger EH; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA., Finan C; Institute of Cardiovascular Science, University College London, London, UK., Garnier S; Sorbonne Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, ICAN Institute for Cardiometabolism and Nutrition, Paris, France., Ghouse J; Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Giedraitis V; Department of Public Health and Caring Sciences, Geriatrics, Uppsala, Sweden., Guðbjartsson DF; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Haggerty CM; Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA., Halliday BP; National Heart and Lung Institute, Imperial College London, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Helgadottir A; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Hemingway H; Institute of Health Informatics, University College London, London, UK.; Health Data Research UK, University College London, London, UK., Hillege HL; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Kardys I; Erasmus MC, Cardiovascular Institute, Thorax Center, Department of Cardiology, Utrecht, the Netherlands., Lind L; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Lindgren CM; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Lowery BD; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA., Manisty C; Institute of Cardiovascular Science, University College London, London, UK.; Barts Heart Centre, St Bartholomew's Hospital, London, UK., Margulies KB; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Moon JC; Institute of Cardiovascular Science, University College London, London, UK.; Barts Heart Centre, St Bartholomew's Hospital, London, UK., Mordi IR; Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK., Morley MP; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Morris AD; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK., Morris AP; Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK., Morton L; Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA., Noursadeghi M; Research Department of Infection, Division of Infection and Immunity, University College London, London, UK., Ostrowski SR; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen University Hospital, Copenhagen, Denmark., Owens AT; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Palmer CNA; Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK., Pantazis A; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Pedersen OBV; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen University Hospital, Copenhagen, Denmark.; Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark., Prasad SK; National Heart and Lung Institute, Imperial College London, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Shekhar A; Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA., Smelser DT; Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA., Srinivasan S; Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK., Stefansson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Department of Medicine, University of Iceland, Reykjavik, Iceland., Sveinbjörnsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Syrris P; Institute of Cardiovascular Science, University College London, London, UK., Tammesoo ML; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Tayal U; National Heart and Lung Institute, Imperial College London, London, UK.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK., Teder-Laving M; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Thorgeirsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Department of Medicine, University of Iceland, Reykjavik, Iceland., Thorsteinsdottir U; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Department of Medicine, University of Iceland, Reykjavik, Iceland., Tragante V; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Trégouët DA; Laboratory of Excellence GENMED (Medical Genomics), Paris, France.; Univ. Bordeaux, INSERM, BPH, Bordeaux, France., Treibel TA; Institute of Cardiovascular Science, University College London, London, UK.; Barts Heart Centre, St Bartholomew's Hospital, London, UK., Ullum H; Statens Serum Institut, Copenhagen, Denmark., Valdes AM; Injury, Recovery and Inflammation Sciences, School of Medicine, University of Nottingham, Nottingham, UK., van Setten J; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands., van Vugt M; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands., Veluchamy A; Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK., Verschuren WMM; Department Life Course, Lifestyle and Health, Centre for Prevention, Lifestyle and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands., Villard E; Sorbonne Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, ICAN Institute for Cardiometabolism and Nutrition, Paris, France., Yang Y; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Asselbergs FW; Institute of Cardiovascular Science, University College London, London, UK.; The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.; Department of Cardiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Cappola TP; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Dube MP; Montreal Heart Institute, Montreal Heart Institute, Montreal, Quebec, Canada.; Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada., Dunn ME; Cardiovascular Research, Regeneron Pharmaceuticals, Tarrytown, NY, USA., Ellinor PT; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Hingorani AD; Institute of Cardiovascular Science, University College London, London, UK., Lang CC; Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.; Tuanku Muhriz Chair, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia., Samani NJ; Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK., Shah SH; Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, USA.; Duke Clinical Research Institute, Durham, NC, USA.; Duke Molecular Physiology Institute, Durham, NC, USA., Smith JG; Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.; Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and Sahlgrenska University Hospital, Gothenburg, Sweden.; Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden., Vasan RS; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.; Sections of Cardiology, Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA., O'Regan DP; MRC Laboratory of Medical Sciences, London, UK., Holm H; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Noseda M; National Heart and Lung Institute, Imperial College London, London, UK., Wells Q; Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA., Ware JS; National Heart and Lung Institute, Imperial College London, London, UK. j.ware@imperial.ac.uk.; MRC Laboratory of Medical Sciences, London, UK. j.ware@imperial.ac.uk.; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK. j.ware@imperial.ac.uk.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. j.ware@imperial.ac.uk., Lumbers RT; Institute of Health Informatics, University College London, London, UK. t.lumbers@ucl.ac.uk.; Health Data Research UK, University College London, London, UK. t.lumbers@ucl.ac.uk.; British Heart Foundation Data Science Centre, London, UK. t.lumbers@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature genetics [Nat Genet] 2024 Dec; Vol. 56 (12), pp. 2646-2658. Date of Electronic Publication: 2024 Nov 21.
DOI:	10.1038/s41588-024-01952-y
Abstrakt:	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. Competing Interests: Competing interests: S.L.Z. has acted as a consultant for Health Lumen. A.H. and R.T.L. have received funding from Pfizer Inc. R.T.L. has performed paid consultancy for Health Lumen and Fitfile Ltd. J.S.W. has acted as a consultant for MyoKardia, Pfizer, Foresite Labs and Health Lumen and received institutional support from Bristol Myers Squibb and Pfizer Inc. P.C. has received personal fees for consultancies, outside the present work, for Amicus, Pfizer Inc., Owkin and Bristol Myers Squibb. M.-P.D. declares holding equity in Dalcor Pharmaceuticals, unrelated to this work. The authors who are affiliated with deCODE genetics/Amgen Inc. and Regeneron Pharmaceuticals declare competing financial interests as employees. The other authors declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
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