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


Journal article


R. Tadros, C. Francis, Xiao Xu, A. Vermeer, A. Harper, R. Huurman, Ken Kelu Bisabu, R. Walsh, E. Hoorntje, W. T. te Rijdt, R. Buchan, Hannah G. van Velzen, M. V. van Slegtenhorst, J. Vermeulen, J. Offerhaus, Wenjia Bai, A. de Marvao, N. Lahrouchi, L. Beekman, J. Karper, J. Veldink, E. Kayvanpour, A. Pantazis, A. Baksi, N. Whiffin, F. Mazzarotto, G. Sloane, Hideaki Suzuki, D. Schneider-Luftman, P. Elliott, P. Richard, F. Ader, E. Villard, P. Lichtner, T. Meitinger, M. Tanck, J. V. van Tintelen, A. Thain, D. Mccarty, R. Hegele, Jason D. Roberts, Julie Amyot, M. Dubé, J. Cadrin-Tourigny, G. Giraldeau, P. L’allier, P. Garceau, J. Tardif, S. Boekholdt, R. Lumbers, F. Asselbergs, P. Barton, S. Cook, S. Prasad, D. O’Regan, J. van der Velden, K. Verweij, M. Talajic, G. Lettre, Y. Pinto, B. Meder, P. Charron, R. D. de Boer, I. Christiaans, M. Michels, A. Wilde, H. Watkins, P. Matthews, J. Ware, C. Bezzina
Nature Genetics, 2021

Semantic Scholar DOI PubMedCentral PubMed
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APA   Click to copy
Tadros, R., Francis, C., Xu, X., Vermeer, A., Harper, A., Huurman, R., … Bezzina, C. (2021). Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nature Genetics.


Chicago/Turabian   Click to copy
Tadros, R., C. Francis, Xiao Xu, A. Vermeer, A. Harper, R. Huurman, Ken Kelu Bisabu, et al. “Shared Genetic Pathways Contribute to Risk of Hypertrophic and Dilated Cardiomyopathies with Opposite Directions of Effect.” Nature Genetics (2021).


MLA   Click to copy
Tadros, R., et al. “Shared Genetic Pathways Contribute to Risk of Hypertrophic and Dilated Cardiomyopathies with Opposite Directions of Effect.” Nature Genetics, 2021.


BibTeX   Click to copy

@article{r2021a,
  title = {Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect},
  year = {2021},
  journal = {Nature Genetics},
  author = {Tadros, R. and Francis, C. and Xu, Xiao and Vermeer, A. and Harper, A. and Huurman, R. and Bisabu, Ken Kelu and Walsh, R. and Hoorntje, E. and te Rijdt, W. T. and Buchan, R. and van Velzen, Hannah G. and van Slegtenhorst, M. V. and Vermeulen, J. and Offerhaus, J. and Bai, Wenjia and de Marvao, A. and Lahrouchi, N. and Beekman, L. and Karper, J. and Veldink, J. and Kayvanpour, E. and Pantazis, A. and Baksi, A. and Whiffin, N. and Mazzarotto, F. and Sloane, G. and Suzuki, Hideaki and Schneider-Luftman, D. and Elliott, P. and Richard, P. and Ader, F. and Villard, E. and Lichtner, P. and Meitinger, T. and Tanck, M. and van Tintelen, J. V. and Thain, A. and Mccarty, D. and Hegele, R. and Roberts, Jason D. and Amyot, Julie and Dubé, M. and Cadrin-Tourigny, J. and Giraldeau, G. and L’allier, P. and Garceau, P. and Tardif, J. and Boekholdt, S. and Lumbers, R. and Asselbergs, F. and Barton, P. and Cook, S. and Prasad, S. and O’Regan, D. and van der Velden, J. and Verweij, K. and Talajic, M. and Lettre, G. and Pinto, Y. and Meder, B. and Charron, P. and de Boer, R. D. and Christiaans, I. and Michels, M. and Wilde, A. and Watkins, H. and Matthews, P. and Ware, J. and Bezzina, C.}
}

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. Genome-wide analyses identify multiple loci associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular (LV) traits. Cardiomyopathies exhibit strong genetic correlations with LV traits, with opposing effects in HCM and DCM.