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

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 (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine...

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Autores principales: Tadros, Rafik, Francis, Catherine, Xu, Xiao, Vermeer, Alexa M. C., Harper, Andrew R., Huurman, Roy, Bisabu, Ken Kelu, Walsh, Roddy, Hoorntje, Edgar T., te Rijdt, Wouter P., Buchan, Rachel J., van Velzen, Hannah G., van Slegtenhorst, Marjon A., Vermeulen, Jentien M., Offerhaus, Joost Allard, Bai, Wenjia, de Marvao, Antonio, Lahrouchi, Najim, Beekman, Leander, Karper, Jacco C., Veldink, Jan H., Kayvanpour, Elham, Pantazis, Antonis, Baksi, A. John, Whiffin, Nicola, Mazzarotto, Francesco, Sloane, Geraldine, Suzuki, Hideaki, Schneider-Luftman, Deborah, Elliott, Paul, Richard, Pascale, Ader, Flavie, Villard, Eric, Lichtner, Peter, Meitinger, Thomas, Tanck, Michael W. T., van Tintelen, J. Peter, Thain, Andrew, McCarty, David, Hegele, Robert A., Roberts, Jason D., Amyot, Julie, Dubé, Marie-Pierre, Cadrin-Tourigny, Julia, Giraldeau, Geneviève, L’Allier, Philippe L., Garceau, Patrick, Tardif, Jean-Claude, Boekholdt, S. Matthijs, Lumbers, R. Thomas, Asselbergs, Folkert W., Barton, Paul J. R., Cook, Stuart A., Prasad, Sanjay K., O’Regan, Declan P., van der Velden, Jolanda, Verweij, Karin J. H., Talajic, Mario, Lettre, Guillaume, Pinto, Yigal M., Meder, Benjamin, Charron, Philippe, de Boer, Rudolf A., Christiaans, Imke, Michels, Michelle, Wilde, Arthur A. M., Watkins, Hugh, Matthews, Paul M., Ware, James S., Bezzina, Connie R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259/
https://www.ncbi.nlm.nih.gov/pubmed/33495596
http://dx.doi.org/10.1038/s41588-020-00762-2
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author Tadros, Rafik
Francis, Catherine
Xu, Xiao
Vermeer, Alexa M. C.
Harper, Andrew R.
Huurman, Roy
Bisabu, Ken Kelu
Walsh, Roddy
Hoorntje, Edgar T.
te Rijdt, Wouter P.
Buchan, Rachel J.
van Velzen, Hannah G.
van Slegtenhorst, Marjon A.
Vermeulen, Jentien M.
Offerhaus, Joost Allard
Bai, Wenjia
de Marvao, Antonio
Lahrouchi, Najim
Beekman, Leander
Karper, Jacco C.
Veldink, Jan H.
Kayvanpour, Elham
Pantazis, Antonis
Baksi, A. John
Whiffin, Nicola
Mazzarotto, Francesco
Sloane, Geraldine
Suzuki, Hideaki
Schneider-Luftman, Deborah
Elliott, Paul
Richard, Pascale
Ader, Flavie
Villard, Eric
Lichtner, Peter
Meitinger, Thomas
Tanck, Michael W. T.
van Tintelen, J. Peter
Thain, Andrew
McCarty, David
Hegele, Robert A.
Roberts, Jason D.
Amyot, Julie
Dubé, Marie-Pierre
Cadrin-Tourigny, Julia
Giraldeau, Geneviève
L’Allier, Philippe L.
Garceau, Patrick
Tardif, Jean-Claude
Boekholdt, S. Matthijs
Lumbers, R. Thomas
Asselbergs, Folkert W.
Barton, Paul J. R.
Cook, Stuart A.
Prasad, Sanjay K.
O’Regan, Declan P.
van der Velden, Jolanda
Verweij, Karin J. H.
Talajic, Mario
Lettre, Guillaume
Pinto, Yigal M.
Meder, Benjamin
Charron, Philippe
de Boer, Rudolf A.
Christiaans, Imke
Michels, Michelle
Wilde, Arthur A. M.
Watkins, Hugh
Matthews, Paul M.
Ware, James S.
Bezzina, Connie R.
author_facet Tadros, Rafik
Francis, Catherine
Xu, Xiao
Vermeer, Alexa M. C.
Harper, Andrew R.
Huurman, Roy
Bisabu, Ken Kelu
Walsh, Roddy
Hoorntje, Edgar T.
te Rijdt, Wouter P.
Buchan, Rachel J.
van Velzen, Hannah G.
van Slegtenhorst, Marjon A.
Vermeulen, Jentien M.
Offerhaus, Joost Allard
Bai, Wenjia
de Marvao, Antonio
Lahrouchi, Najim
Beekman, Leander
Karper, Jacco C.
Veldink, Jan H.
Kayvanpour, Elham
Pantazis, Antonis
Baksi, A. John
Whiffin, Nicola
Mazzarotto, Francesco
Sloane, Geraldine
Suzuki, Hideaki
Schneider-Luftman, Deborah
Elliott, Paul
Richard, Pascale
Ader, Flavie
Villard, Eric
Lichtner, Peter
Meitinger, Thomas
Tanck, Michael W. T.
van Tintelen, J. Peter
Thain, Andrew
McCarty, David
Hegele, Robert A.
Roberts, Jason D.
Amyot, Julie
Dubé, Marie-Pierre
Cadrin-Tourigny, Julia
Giraldeau, Geneviève
L’Allier, Philippe L.
Garceau, Patrick
Tardif, Jean-Claude
Boekholdt, S. Matthijs
Lumbers, R. Thomas
Asselbergs, Folkert W.
Barton, Paul J. R.
Cook, Stuart A.
Prasad, Sanjay K.
O’Regan, Declan P.
van der Velden, Jolanda
Verweij, Karin J. H.
Talajic, Mario
Lettre, Guillaume
Pinto, Yigal M.
Meder, Benjamin
Charron, Philippe
de Boer, Rudolf A.
Christiaans, Imke
Michels, Michelle
Wilde, Arthur A. M.
Watkins, Hugh
Matthews, Paul M.
Ware, James S.
Bezzina, Connie R.
author_sort Tadros, Rafik
collection PubMed
description 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 (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 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 contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS 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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spelling pubmed-76112592021-07-25 Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect Tadros, Rafik Francis, Catherine Xu, Xiao Vermeer, Alexa M. C. Harper, Andrew R. Huurman, Roy Bisabu, Ken Kelu Walsh, Roddy Hoorntje, Edgar T. te Rijdt, Wouter P. Buchan, Rachel J. van Velzen, Hannah G. van Slegtenhorst, Marjon A. Vermeulen, Jentien M. Offerhaus, Joost Allard Bai, Wenjia de Marvao, Antonio Lahrouchi, Najim Beekman, Leander Karper, Jacco C. Veldink, Jan H. Kayvanpour, Elham Pantazis, Antonis Baksi, A. John Whiffin, Nicola Mazzarotto, Francesco Sloane, Geraldine Suzuki, Hideaki Schneider-Luftman, Deborah Elliott, Paul Richard, Pascale Ader, Flavie Villard, Eric Lichtner, Peter Meitinger, Thomas Tanck, Michael W. T. van Tintelen, J. Peter Thain, Andrew McCarty, David Hegele, Robert A. Roberts, Jason D. Amyot, Julie Dubé, Marie-Pierre Cadrin-Tourigny, Julia Giraldeau, Geneviève L’Allier, Philippe L. Garceau, Patrick Tardif, Jean-Claude Boekholdt, S. Matthijs Lumbers, R. Thomas Asselbergs, Folkert W. Barton, Paul J. R. Cook, Stuart A. Prasad, Sanjay K. O’Regan, Declan P. van der Velden, Jolanda Verweij, Karin J. H. Talajic, Mario Lettre, Guillaume Pinto, Yigal M. Meder, Benjamin Charron, Philippe de Boer, Rudolf A. Christiaans, Imke Michels, Michelle Wilde, Arthur A. M. Watkins, Hugh Matthews, Paul M. Ware, James S. Bezzina, Connie R. Nat Genet Article 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 (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 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 contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS 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. 2021-02-01 2021-01-25 /pmc/articles/PMC7611259/ /pubmed/33495596 http://dx.doi.org/10.1038/s41588-020-00762-2 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Tadros, Rafik
Francis, Catherine
Xu, Xiao
Vermeer, Alexa M. C.
Harper, Andrew R.
Huurman, Roy
Bisabu, Ken Kelu
Walsh, Roddy
Hoorntje, Edgar T.
te Rijdt, Wouter P.
Buchan, Rachel J.
van Velzen, Hannah G.
van Slegtenhorst, Marjon A.
Vermeulen, Jentien M.
Offerhaus, Joost Allard
Bai, Wenjia
de Marvao, Antonio
Lahrouchi, Najim
Beekman, Leander
Karper, Jacco C.
Veldink, Jan H.
Kayvanpour, Elham
Pantazis, Antonis
Baksi, A. John
Whiffin, Nicola
Mazzarotto, Francesco
Sloane, Geraldine
Suzuki, Hideaki
Schneider-Luftman, Deborah
Elliott, Paul
Richard, Pascale
Ader, Flavie
Villard, Eric
Lichtner, Peter
Meitinger, Thomas
Tanck, Michael W. T.
van Tintelen, J. Peter
Thain, Andrew
McCarty, David
Hegele, Robert A.
Roberts, Jason D.
Amyot, Julie
Dubé, Marie-Pierre
Cadrin-Tourigny, Julia
Giraldeau, Geneviève
L’Allier, Philippe L.
Garceau, Patrick
Tardif, Jean-Claude
Boekholdt, S. Matthijs
Lumbers, R. Thomas
Asselbergs, Folkert W.
Barton, Paul J. R.
Cook, Stuart A.
Prasad, Sanjay K.
O’Regan, Declan P.
van der Velden, Jolanda
Verweij, Karin J. H.
Talajic, Mario
Lettre, Guillaume
Pinto, Yigal M.
Meder, Benjamin
Charron, Philippe
de Boer, Rudolf A.
Christiaans, Imke
Michels, Michelle
Wilde, Arthur A. M.
Watkins, Hugh
Matthews, Paul M.
Ware, James S.
Bezzina, Connie R.
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
title Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
title_full Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
title_fullStr Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
title_full_unstemmed Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
title_short Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
title_sort shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259/
https://www.ncbi.nlm.nih.gov/pubmed/33495596
http://dx.doi.org/10.1038/s41588-020-00762-2
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