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Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.
Tadros, Rafik; Francis, Catherine; Xu, Xiao; Vermeer, Alexa M C; Harper, Andrew R; Huurman, Roy; Kelu Bisabu, Ken; Walsh, Roddy; Hoorntje, Edgar T; Te Rijdt, Wouter P; Buchan, Rachel J; van Velzen, Hannah G; van Slegtenhorst, Marjon A; Vermeulen, Jentien M; Offerhaus, Joost Allard; Bai, Wenjia; de Marvao, Antonio; Lahrouchi, Najim; Beekman, Leander; Karper, Jacco C; Veldink, Jan H; Kayvanpour, Elham; Pantazis, Antonis; Baksi, A John; Whiffin, Nicola; Mazzarotto, Francesco; Sloane, Geraldine; Suzuki, Hideaki; Schneider-Luftman, Deborah; Elliott, Paul; Richard, Pascale; Ader, Flavie; Villard, Eric; Lichtner, Peter; Meitinger, Thomas; Tanck, Michael W T; van Tintelen, J Peter; Thain, Andrew; McCarty, David; Hegele, Robert A; Roberts, Jason D; Amyot, Julie; Dubé, Marie-Pierre; Cadrin-Tourigny, Julia; Giraldeau, Geneviève; L'Allier, Philippe L; Garceau, Patrick; Tardif, Jean-Claude; Boekholdt, S Matthijs; Lumbers, R Thomas.
Afiliação
  • Tadros R; Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. rafik.tadros@umontreal.ca.
  • Francis C; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. rafik.tadros@umontreal.ca.
  • Xu X; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • Vermeer AMC; National Heart and Lung Institute, Imperial College London, London, UK.
  • Harper AR; MRC London Institute of Medical Sciences, Imperial College London, London, UK.
  • Huurman R; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Kelu Bisabu K; Department of Clinical Genetics, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Walsh R; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART).
  • Hoorntje ET; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Te Rijdt WP; Wellcome Centre for Human Genetics, Oxford, UK.
  • Buchan RJ; Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • van Velzen HG; Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.
  • van Slegtenhorst MA; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Vermeulen JM; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • Offerhaus JA; Netherlands Heart Institute, Utrecht, the Netherlands.
  • Bai W; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • de Marvao A; Netherlands Heart Institute, Utrecht, the Netherlands.
  • Lahrouchi N; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • Beekman L; National Heart and Lung Institute, Imperial College London, London, UK.
  • Karper JC; Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Veldink JH; Department of Clinical Genetics, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • Kayvanpour E; Department of Psychiatry, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Pantazis A; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Baksi AJ; Data Science Institute, Imperial College London, London, UK.
  • Whiffin N; Department of Brain Sciences and UK Dementia Research Institute at Imperial College London, Hammersmith Hospital, Imperial College London, London, UK.
  • Mazzarotto F; MRC London Institute of Medical Sciences, Imperial College London, London, UK.
  • Sloane G; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Suzuki H; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Schneider-Luftman D; Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • Elliott P; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • Richard P; Institute for Cardiomyopathies, Heidelberg Heart Center, University of Heidelberg, Heidelberg, Germany.
  • Ader F; DZHK (German Center for Cardiovascular Research), Berlin, Germany.
  • Villard E; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • Lichtner P; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • Meitinger T; National Heart and Lung Institute, Imperial College London, London, UK.
  • Tanck MWT; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • van Tintelen JP; National Heart and Lung Institute, Imperial College London, London, UK.
  • Thain A; MRC London Institute of Medical Sciences, Imperial College London, London, UK.
  • McCarty D; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • Hegele RA; National Heart and Lung Institute, Imperial College London, London, UK.
  • Roberts JD; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Amyot J; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
  • Dubé MP; Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
  • Cadrin-Tourigny J; National Heart and Lung Institute, Imperial College London, London, UK.
  • Giraldeau G; Department of Brain Sciences and UK Dementia Research Institute at Imperial College London, Hammersmith Hospital, Imperial College London, London, UK.
  • L'Allier PL; Department of Cardiovascular Medicine, Tohoku University Hospital, Seiryo, Aoba, Sendai, Japan.
  • Garceau P; Tohoku Medical Megabank Organization, Tohoku University, Seiryo, Aoba, Sendai, Japan.
  • Tardif JC; The Francis Crick Institute, London, UK.
  • Boekholdt SM; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
  • Lumbers RT; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
Nat Genet ; 53(2): 128-134, 2021 02.
Article em En | MEDLINE | ID: mdl-33495596
ABSTRACT
The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Cardiomiopatia Hipertrófica / Cardiomiopatia Dilatada Tipo de estudo: Clinical_trials / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Cardiomiopatia Hipertrófica / Cardiomiopatia Dilatada Tipo de estudo: Clinical_trials / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá