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. Karper; Jan 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 Dubé; Julia Cadrin-Tourigny; Geneviève 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

doi:10.1038/s41588-020-00762-2

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 Dubé, Julia Cadrin-Tourigny, Geneviève 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 journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	128-134
Journal	Nature Genetics
Volume	53
Issue number	2
DOIs	https://doi.org/10.1038/s41588-020-00762-2
Publication status	Published - 1 Feb 2021

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Tadros, R., Francis, C., Xu, X., Vermeer, A. M. C., Harper, A. R., Huurman, R., Kelu Bisabu, K., Walsh, R., Hoorntje, E. T., te Rijdt, W. P., Buchan, R. J., van Velzen, H. G., van Slegtenhorst, M. A., Vermeulen, J. M., Offerhaus, J. A., Bai, W., de Marvao, A., Lahrouchi, N., Beekman, L., ... Bezzina, C. R. (2021). Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nature Genetics, 53(2), 128-134. https://doi.org/10.1038/s41588-020-00762-2

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title = "Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect",

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.",

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

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doi = "10.1038/s41588-020-00762-2",

language = "English",

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pages = "128--134",

journal = "Nature Genetics",

issn = "1061-4036",

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Tadros, R, Francis, C, Xu, X, Vermeer, AMC, Harper, AR, Huurman, R, Kelu Bisabu, K, Walsh, R, Hoorntje, ET, te Rijdt, WP, Buchan, RJ, van Velzen, HG, van Slegtenhorst, MA, Vermeulen, JM, Offerhaus, JA, Bai, W, de Marvao, A, Lahrouchi, N, Beekman, L, Karper, JC, Veldink, JH, Kayvanpour, E, Pantazis, A, Baksi, AJ, Whiffin, N, Mazzarotto, F, Sloane, G, Suzuki, H, Schneider-Luftman, D, Elliott, P, Richard, P, Ader, F, Villard, E, Lichtner, P, Meitinger, T, Tanck, MWT, van Tintelen, JP, Thain, A, McCarty, D, Hegele, RA, Roberts, JD, Amyot, J, Dubé, M-P, Cadrin-Tourigny, J, Giraldeau, G, l’Allier, PL, Garceau, P, Tardif, J-C, Boekholdt, SM, Lumbers, RT, Asselbergs, FW, Barton, PJR, Cook, SA, Prasad, SK, O’Regan, DP, van der Velden, J, Verweij, KJH, Talajic, M, Lettre, G, Pinto, YM, Meder, B, Charron, P, de Boer, RA, Christiaans, I, Michels, M, Wilde, AAM, Watkins, H, Matthews, PM, Ware, JS & Bezzina, CR 2021, 'Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect', Nature Genetics, vol. 53, no. 2, pp. 128-134. https://doi.org/10.1038/s41588-020-00762-2

TY - JOUR

T1 - Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

AU - Tadros, Rafik

AU - Francis, Catherine

AU - Xu, Xiao

AU - Vermeer, Alexa M. C.

AU - Harper, Andrew R.

AU - Huurman, Roy

AU - Kelu Bisabu, Ken

AU - Walsh, Roddy

AU - Hoorntje, Edgar T.

AU - te Rijdt, Wouter P.

AU - Buchan, Rachel J.

AU - van Velzen, Hannah G.

AU - van Slegtenhorst, Marjon A.

AU - Vermeulen, Jentien M.

AU - Offerhaus, Joost Allard

AU - Bai, Wenjia

AU - de Marvao, Antonio

AU - Lahrouchi, Najim

AU - Beekman, Leander

AU - Karper, Jacco C.

AU - Veldink, Jan H.

AU - Kayvanpour, Elham

AU - Pantazis, Antonis

AU - Baksi, A. John

AU - Whiffin, Nicola

AU - Mazzarotto, Francesco

AU - Sloane, Geraldine

AU - Suzuki, Hideaki

AU - Schneider-Luftman, Deborah

AU - Elliott, Paul

AU - Richard, Pascale

AU - Ader, Flavie

AU - Villard, Eric

AU - Lichtner, Peter

AU - Meitinger, Thomas

AU - Tanck, Michael W. T.

AU - van Tintelen, J. Peter

AU - Thain, Andrew

AU - McCarty, David

AU - Hegele, Robert A.

AU - Roberts, Jason D.

AU - Amyot, Julie

AU - Dubé, Marie-Pierre

AU - Cadrin-Tourigny, Julia

AU - Giraldeau, Geneviève

AU - l’Allier, Philippe L.

AU - Garceau, Patrick

AU - Tardif, Jean-Claude

AU - Boekholdt, S. Matthijs

AU - Lumbers, R. Thomas

AU - Asselbergs, Folkert W.

AU - Barton, Paul J. R.

AU - Cook, Stuart A.

AU - Prasad, Sanjay K.

AU - O’Regan, Declan P.

AU - van der Velden, Jolanda

AU - Verweij, Karin J. H.

AU - Talajic, Mario

AU - Lettre, Guillaume

AU - Pinto, Yigal M.

AU - Meder, Benjamin

AU - Charron, Philippe

AU - de Boer, Rudolf A.

AU - Christiaans, Imke

AU - Michels, Michelle

AU - Wilde, Arthur A. M.

AU - Watkins, Hugh

AU - Matthews, Paul M.

AU - Ware, James S.

AU - Bezzina, Connie R.

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/33495596

U2 - 10.1038/s41588-020-00762-2

DO - 10.1038/s41588-020-00762-2

M3 - Article

C2 - 33495596

SN - 1061-4036

VL - 53

SP - 128

EP - 134

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

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