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

Rafik Tadros, Catherine Francis, Xiao Xu, Alexa M. C. Vermeer, Andrew R. Harper, Roy Huurman, Ken Kelu Bisabu, Roddy Walsh, Edgar T. Hoorntje, Wouter P. te Rijdt, Rachel J. Buchan, Hannah G. van Velzen, Marjon A. van Slegtenhorst, Jentien M. Vermeulen, Joost Allard Offerhaus, Wenjia Bai, Antonio de Marvao, Najim Lahrouchi, Leander Beekman, Jacco C. KarperJan H. Veldink, Elham Kayvanpour, Antonis Pantazis, A. John Baksi, Nicola Whiffin, Francesco Mazzarotto, Geraldine Sloane, Hideaki Suzuki, Deborah Schneider-Luftman, Paul Elliott, Pascale Richard, Flavie Ader, Eric Villard, Peter Lichtner, Thomas Meitinger, Michael W. T. Tanck, J. Peter van Tintelen, Andrew Thain, David McCarty, Robert A. Hegele, Jason D. Roberts, Julie Amyot, Marie-Pierre Dube, Julia Cadrin-Tourigny, Genevieve Giraldeau, Philippe L. L'Allier, Patrick Garceau, Jean-Claude Tardif, S. Matthijs Boekholdt, R. Thomas Lumbers, Folkert W. Asselbergs, Paul J. R. Barton, Stuart A. Cook, Sanjay K. Prasad, Declan P. O'Regan, Jolanda van der Velden, Karin J. H. Verweij, Mario Talajic, Guillaume Lettre, Yigal M. Pinto, Benjamin Meder, Philippe Charron, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Arthur A. M. Wilde, Hugh Watkins, Paul M. Matthews, James S. Ware, Connie R. Bezzina*

*Corresponding author for this work

Research output: Contribution to journalLetterAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)128-134
Number of pages24
JournalNature Genetics
Volume53
Issue number2
DOIs
Publication statusPublished - Feb-2021

Keywords

  • 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

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