Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Cardiomyopathy, Dilated / genetics Cardiomyopathy, Hypertrophic / genetics Case-Control Studies Gene Frequency Genetic Predisposition to Disease Genome-Wide Association Study Heart Ventricles / physiopathology Humans Kaplan-Meier Estimate Linkage Disequilibrium Polymorphism, Single Nucleotide Quantitative Trait Loci Ventricular Function, Left / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
02 2021
Historique:
received: 28 02 2020
accepted: 10 12 2020
pubmed: 27 1 2021
medline: 5 3 2021
entrez: 26 1 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-020-00762-2 PMID: 33495596 PMC: PMC7611259
pubmed: 33495596
doi: 10.1038/s41588-020-00762-2
pii: 10.1038/s41588-020-00762-2
pmc: PMC7611259
mid: EMS114661
doi:

Types de publication

Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

128-134

Subventions

Organisme : Medical Research Council
ID : MR/K501013/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107469
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1605/13
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N026934/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17114
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107469/Z/15/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/19/6/34387
Pays : United Kingdom
Organisme : Medical Research Council
ID : G9901399
Pays : United Kingdom
Organisme : ZonMw
ID : ZONMW_91815610
Pays : Netherlands
Organisme : British Heart Foundation
ID : RE/18/4/34215
Pays : United Kingdom
Organisme : Medical Research Council
ID : G9409531
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900897
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/15/81/31817
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1102/19
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 087183
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S003754/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1102/20
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300665
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U120085815
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0601966
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RE/13/1/30181
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532/Z/09/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/9/33887
Pays : United Kingdom
Organisme : Medical Research Council
ID : G9409634
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0100811
Pays : United Kingdom
Organisme : British Heart Foundation
ID : SP/17/11/32885
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M024903/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : NH/17/1/32725
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

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Auteurs

Rafik Tadros (R)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. rafik.tadros@umontreal.ca.
Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. rafik.tadros@umontreal.ca.
ORCID: 0000-0002-1472-0258

Catherine Francis (C)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.

Xiao Xu (X)

MRC London Institute of Medical Sciences, Imperial College London, London, UK.

Alexa M C Vermeer (AMC)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
Department of Clinical Genetics, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART).

Andrew R Harper (AR)

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Wellcome Centre for Human Genetics, Oxford, UK.
ORCID: 0000-0001-5327-0328

Roy Huurman (R)

Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.
ORCID: 0000-0001-7405-8668

Ken Kelu Bisabu (K)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.
ORCID: 0000-0003-1453-177X

Roddy Walsh (R)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
ORCID: 0000-0001-5092-8825

Edgar T Hoorntje (ET)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Netherlands Heart Institute, Utrecht, the Netherlands.

Wouter P Te Rijdt (WP)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Netherlands Heart Institute, Utrecht, the Netherlands.

Rachel J Buchan (RJ)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
ORCID: 0000-0003-2490-9289

Hannah G van Velzen (HG)

Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.

Marjon A van Slegtenhorst (MA)

Department of Clinical Genetics, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.

Jentien M Vermeulen (JM)

Department of Psychiatry, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

Joost Allard Offerhaus (JA)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

Wenjia Bai (W)

Data Science Institute, Imperial College London, London, UK.
Department of Brain Sciences and UK Dementia Research Institute at Imperial College London, Hammersmith Hospital, Imperial College London, London, UK.
ORCID: 0000-0003-2943-7698

Antonio de Marvao (A)

MRC London Institute of Medical Sciences, Imperial College London, London, UK.

Najim Lahrouchi (N)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
ORCID: 0000-0003-1753-452X

Leander Beekman (L)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

Jacco C Karper (JC)

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Jan H Veldink (JH)

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
ORCID: 0000-0001-5572-9657

Elham Kayvanpour (E)

Institute for Cardiomyopathies, Heidelberg Heart Center, University of Heidelberg, Heidelberg, Germany.
DZHK (German Center for Cardiovascular Research), Berlin, Germany.

Antonis Pantazis (A)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.

A John Baksi (AJ)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.

Nicola Whiffin (N)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
MRC London Institute of Medical Sciences, Imperial College London, London, UK.
ORCID: 0000-0003-1554-6594

Francesco Mazzarotto (F)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
ORCID: 0000-0002-6159-9980

Geraldine Sloane (G)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.

Hideaki Suzuki (H)

Department of Brain Sciences and UK Dementia Research Institute at Imperial College London, Hammersmith Hospital, Imperial College London, London, UK.
Department of Cardiovascular Medicine, Tohoku University Hospital, Seiryo, Aoba, Sendai, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Seiryo, Aoba, Sendai, Japan.
ORCID: 0000-0002-0410-6940

Deborah Schneider-Luftman (D)

The Francis Crick Institute, London, UK.
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

Paul Elliott (P)

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
ORCID: 0000-0002-7511-5684

Pascale Richard (P)

Service de biochimie métabolique, UF de cardiogénétique et myogénétique moléculaire et cellulaire, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
INSERM, UMR_S 1166 and ICAN Institute for Cardiometabolism and Nutrition, Faculté de Médecine, Sorbonne Université, Paris, France.

Flavie Ader (F)

Service de biochimie métabolique, UF de cardiogénétique et myogénétique moléculaire et cellulaire, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
INSERM, UMR_S 1166 and ICAN Institute for Cardiometabolism and Nutrition, Faculté de Médecine, Sorbonne Université, Paris, France.
Faculté de Pharmacie, Université de Paris, Paris, France.
ORCID: 0000-0001-7891-3385

Eric Villard (E)

INSERM, UMR_S 1166 and ICAN Institute for Cardiometabolism and Nutrition, Faculté de Médecine, Sorbonne Université, Paris, France.

Peter Lichtner (P)

Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.

Thomas Meitinger (T)

Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
Klinikum rechts der Isar der TU Muenchen School of Medicine, Institute of Human Genetics, Munich, Germany.
DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
ORCID: 0000-0002-8838-8403

Michael W T Tanck (MWT)

Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Amsterdam Public Health (APH), Amsterdam UMC, Amsterdam, the Netherlands.
ORCID: 0000-0001-9828-4459

J Peter van Tintelen (JP)

Department of Clinical Genetics, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
ORCID: 0000-0003-3854-6749

Andrew Thain (A)

Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

David McCarty (D)

Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Robert A Hegele (RA)

Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
ORCID: 0000-0003-2861-5325

Jason D Roberts (JD)

Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Julie Amyot (J)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Marie-Pierre Dubé (MP)

Montreal Heart Institute Research Center, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.
ORCID: 0000-0001-8442-4393

Julia Cadrin-Tourigny (J)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Geneviève Giraldeau (G)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Philippe L L'Allier (PL)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Patrick Garceau (P)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Jean-Claude Tardif (JC)

Montreal Heart Institute Research Center, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

S Matthijs Boekholdt (SM)

Department of Cardiology, University of Amsterdam, Heartcenter, Amsterdam UMC, Amsterdam, the Netherlands.

R Thomas Lumbers (RT)

Institute of Health Informatics, University College London, London, UK.
Health Data Research UK, Gibbs Building, London, UK.
Barts Heart Centre, Saint Bartholomew's Hospital, London, UK.
ORCID: 0000-0002-9077-4741

Folkert W Asselbergs (FW)

Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Institute of Cardiovascular Science and Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK.
ORCID: 0000-0002-1692-8669

Paul J R Barton (PJR)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
ORCID: 0000-0002-1165-7767

Stuart A Cook (SA)

National Heart and Lung Institute, Imperial College London, London, UK.
MRC London Institute of Medical Sciences, Imperial College London, London, UK.
National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore.
Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.

Sanjay K Prasad (SK)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.

Declan P O'Regan (DP)

MRC London Institute of Medical Sciences, Imperial College London, London, UK.
ORCID: 0000-0002-0691-0270

Jolanda van der Velden (J)

Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, the Netherlands.
ORCID: 0000-0001-5224-5788

Karin J H Verweij (KJH)

Department of Psychiatry, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
ORCID: 0000-0001-9868-7821

Mario Talajic (M)

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Guillaume Lettre (G)

Montreal Heart Institute Research Center, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

Yigal M Pinto (YM)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART).
ORCID: 0000-0002-2836-571X

Benjamin Meder (B)

Institute for Cardiomyopathies, Heidelberg Heart Center, University of Heidelberg, Heidelberg, Germany.

Philippe Charron (P)

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART).
INSERM, UMR_S 1166 and ICAN Institute for Cardiometabolism and Nutrition, Faculté de Médecine, Sorbonne Université, Paris, France.
Département de Génétique, Centre de référence des maladies cardiaques héréditaires ou rares, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
ORCID: 0000-0002-1782-1118

Rudolf A de Boer (RA)

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
ORCID: 0000-0002-4775-9140

Imke Christiaans (I)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Michelle Michels (M)

Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.

Arthur A M Wilde (AAM)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART).

Hugh Watkins (H)

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Wellcome Centre for Human Genetics, Oxford, UK.
ORCID: 0000-0002-5287-9016

Paul M Matthews (PM)

Department of Brain Sciences and UK Dementia Research Institute at Imperial College London, Hammersmith Hospital, Imperial College London, London, UK.
ORCID: 0000-0002-1619-8328

James S Ware (JS)

Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK. j.ware@imperial.ac.uk.
National Heart and Lung Institute, Imperial College London, London, UK. j.ware@imperial.ac.uk.
MRC London Institute of Medical Sciences, Imperial College London, London, UK. j.ware@imperial.ac.uk.
ORCID: 0000-0002-6110-5880

Connie R Bezzina (CR)

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. c.r.bezzina@amsterdamumc.nl.
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), . c.r.bezzina@amsterdamumc.nl.
ORCID: 0000-0002-0633-3514

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Classifications MeSH

questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Laminopathies › Cardiomyopathie dilatée › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Valvulopathies › Maladie de la valve aortique › Cardiomyopathie hypertrophique › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Phénomènes génétiques › Fréquence d'allèle › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Système cardiovasculaire › Coeur › Ventricules cardiaques › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Estimation de Kaplan-Meier › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Phénomènes génétiques › Liaison génétique › Déséquilibre de liaison › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Shared genetic pathways contribute to risk of...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiologiques cardiovasculaires › Fonction ventriculaire › Fonction ventriculaire gauche › Shared genetic pathways contribute to risk of...