1. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
- Author
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Antonio de Marvao, Roddy Walsh, Jean-Claude Tardif, R. Thomas Lumbers, Eric Villard, Rafik Tadros, Peter Lichtner, Catherine Francis, Julie Amyot, Michelle Michels, Hugh Watkins, Julia Cadrin-Tourigny, Najim Lahrouchi, Rudolf A. de Boer, Patrick Garceau, Karin J. H. Verweij, Paul M. Matthews, Paul Elliott, S. Matthijs Boekholdt, Folkert W. Asselbergs, Declan P. O'Regan, Benjamin Meder, Joost A. Offerhaus, Nicola Whiffin, Jacco C. Karper, Jason D. Roberts, Marie-Pierre Dubé, Hideaki Suzuki, James S. Ware, Yigal M. Pinto, Thomas Meitinger, Guillaume Lettre, Hannah G. van Velzen, Arthur A.M. Wilde, Marjon van Slegtenhorst, Francesco Mazzarotto, Wouter P. te Rijdt, Paul J.R. Barton, Sanjay K Prasad, A. John Baksi, Michael W.T. Tanck, Mario Talajic, Roy Huurman, J. Peter van Tintelen, Connie R. Bezzina, Antonis Pantazis, Robert A. Hegele, Jentien M Vermeulen, Rachel Buchan, Imke Christiaans, Jan H. Veldink, Edgar T. Hoorntje, Elham Kayvanpour, Pascale Richard, Geneviève Giraldeau, Flavie Ader, Andrew Thain, Philippe L. L’Allier, Xiao Xu, Leander Beekman, David McCarty, Alexa M.C. Vermeer, Geraldine Sloane, Wenjia Bai, Andrew R. Harper, Jolanda van der Velden, Stuart A. Cook, Ken Kelu Bisabu, Philippe Charron, Deborah Schneider-Luftman, Human Genetics, ACS - Heart failure & arrhythmias, Cardiology, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Compulsivity, Impulsivity & Attention, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, ACS - Amsterdam Cardiovascular Sciences, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Human genetics, Physiology, Cardiovascular Centre (CVC), Clinical Genetics, Wellcome Trust, Department of Health, British Heart Foundation, Engineering & Physical Science Research Council (EPSRC), UK DRI Ltd, The Academy of Medical Sciences, and Imperial College Healthcare NHS Trust- BRC Funding
- Subjects
Linkage disequilibrium ,Cardiomyopathy, Dilated/genetics ,Left ,Cardiomyopathy ,Genome-wide association study ,Kaplan-Meier Estimate ,VARIANTS ,Ventricular Function, Left ,Linkage Disequilibrium ,0302 clinical medicine ,Gene Frequency ,Dilated ,Ventricular Function ,11 Medical and Health Sciences ,Cardiomyopathy, Hypertrophic/genetics ,Genetics & Heredity ,0303 health sciences ,HERITABILITY ,Single Nucleotide ,MENDELIAN RANDOMIZATION ,Cardiology ,cardiovascular system ,HEART ,Life Sciences & Biomedicine ,Ventricular Function, Left/genetics ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,Heart Ventricles ,Quantitative Trait Loci ,Biology ,Quantitative trait locus ,Sudden death ,Polymorphism, Single Nucleotide ,Article ,Heart Ventricles/physiopathology ,03 medical and health sciences ,Internal medicine ,Mendelian randomization ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,GENOME-WIDE ASSOCIATION ,Polymorphism ,030304 developmental biology ,Genetic association ,Science & Technology ,Hypertrophic/genetics ,Left/genetics ,Case-control study ,CONTRACTILITY ,06 Biological Sciences ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Hypertrophic ,Dilated/genetics ,Case-Control Studies ,Genome-Wide Association Study ,030217 neurology & neurosurgery ,Developmental Biology - 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.
- Published
- 2021
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