Journal
NATURE GENETICS
Volume 53, Issue 2, Pages 128-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-00762-2
Keywords
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Categories
Funding
- Canadian Heart Rhythm Society (George Mines Award)
- European Society of Cardiology
- Canadian Institutes of Health Research [169063]
- Fonds de Recherche du Quebec-Sante [135055]
- Philippa and Marvin Carsley Cardiology Chair
- British Heart Foundation Clinical Research Training Fellowship [FS/15/81/31817]
- Medical Research Council London Institute of Medical Sciences
- Medical Research Council Doctoral Training Partnership
- Amsterdam Cardiovascular Sciences fellowship
- Young Talent Program of the Dutch Heart Foundation [CVON PREDICT 2012-10]
- CURE-PLaN (Netherlands Heart Institute) from the Leducq Foundation
- Amsterdam UMC's PhD scholarship
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London
- Medical Research Council, UK
- Academy of Medical Sciences [SGL015/1006]
- Mason Medical Research Trust
- European Research Council (ERC) under the European Union [772376 - EScORIAL]
- German Center for Cardiovascular Research (DZHK) Rotation Grant
- University of Florence
- European Union [777204]
- Japan Society for the Promotion of Science [18K15410]
- UK Med-Bio
- Federation Francaise de Cardiologie
- Ligue contre la cardiomyopathie
- CONNY-MAEVA charitable foundation
- GenMed LABEX
- Dutch Heart Foundation Netherlands Cardiovascular Research Initiative (CVON) [PREDICT2 2018-30, eDETECT 2015-12, DOSIS 2014-40, DOLPHIN-GENESIS 2017-10]
- Jacob J. Wolfe Distinguished Medical Research Chair
- Edith Schulich Vinet Research Chair in Human Genetics
- Martha G. Blackburn Chair in Cardiovascular Research
- Canadian Institutes of Health Research
- Heart and Stroke Foundation of Canada [G-18-0022147]
- Montreal Heart Institute Foundation
- UK Research and Innovation Rutherford Fellowship
- UCL Hospitals NIHR Biomedical Research Centre
- Dutch Heart Foundation [2016T096]
- Netherlands Organization for Health Research and Development (ZonMw)
- Department of Health, UK [HICF-R6-373]
- Medical Research Council
- NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London
- British Heart Foundation Program [RG/19/6/34387]
- Foundation Volksbond Rotterdam
- Monat foundation
- J. C. Edwards Foundation
- Canada Research Chair Program
- DZHK
- German Ministry of Education and Research (CaRNAtion)
- Informatics for Life (Klaus Tschira Foundation)
- European Union
- Else Kroner Fresenius Foundation
- PROMEX charitable foundation
- Wellcome Trust [090532/Z/09/Z, 107469/Z/15/Z]
- BHF Centre of Research Excellence, Oxford [RE/13/1/30181]
- NIHR Oxford Biomedical Research Centre
- National Heart, Lung and Blood Institute [U01HL117006-01A1]
- Edmond J. Safra Foundation
- Lily Safra, an NIHR Senior Investigator Award
- UK Dementia Research Institute
- British Heart Foundation [SP/17/11/32885, RE/18/4/34215]
- Medical Research Council (UK)
- NIHR Royal Brompton Cardiovascular Biomedical Research Unit
- NIHR Imperial College Biomedical Research Centre
- Netherlands Organization for Scientific Research [016.150.610]
- Leducq Foundation [17CVD02]
- Common Fund of the Office of the Director of the National Institutes of Health
- National Cancer Institute (NCI)
- National Human Genome Research Institute (NHGRI)
- National Heart, Lung and Blood Institute (NHLBI)
- National Institute on Drug Abuse (NIDA)
- National Institute of Mental Health (NIMH)
- National Institute of Neorological Disorders and Stroke (NINDS)
- European Union's Horizon 2020 research and innovation program under the ERA-NET Co-fund action [680969]
- Dutch Heart Foundation Netherlands Cardiovascular Research Initiative (PRIME)
- MRC [MC_U120085815, MC_UP_1102/20, MC_UP_1102/19, MR/S003754/1] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [18K15410] Funding Source: KAKEN
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The study found a strong genetic correlation between hypertrophic and dilated cardiomyopathies and left ventricular traits, with opposing genetic effects in the two cardiomyopathies. The research also supported a causal association between increased left ventricular contractility and hypertrophic cardiomyopathy risk.
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 cardiomy-opathies, 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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