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

R Tadros; C Francis; X Xu; A Vermeer; AR Harper; Roy Huurman; KK Bisabu; R Walsh; ET Hoorntje; WP te Rijdt; RJ Buchan; Hannah Velzen; Marjon van Slegtenhorst; JM Vermeulen; JA Offerhaus; WJ Bai; A de Marvao; N Lahrouchi; L Beekman; JC Karper; JH Veldink; E Kayvanpour; A Pantazis; AJ Baksi; N Whiffin; F Mazzarotto; G Sloane; H Suzuki; D Schneider-Luftman; P Elliott; P Richard; F Ader; E Villard; P Lichtner; T Meitinger; MW Tanck; JP Tintelen; A Thain; D McCarty; RA Hegele; JD Roberts; J Amyot; MP Dube; J Cadrin-Tourigny; G Giraldeau; PL L'Allier; P Garceau; JC Tardif; SM Boekholdt; RT Lumbers; FW Asselbergs; PJR Barton; SA Cook; SK Prasad; DP O'Regan; J Velden; KJH Verweij; M Talajic; G Lettre; YM Pinto; B Meder; P Charron; RA de Boer; I Christiaans; Michelle Michels; AA Wilde; H Watkins; PM Matthews; JS Ware; CR Bezzina

doi:10.1038/s41588-020-00762-2

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

R Tadros, C Francis, X Xu, A Vermeer, AR Harper, Roy Huurman, KK Bisabu, R Walsh, ET Hoorntje, WP te Rijdt, RJ Buchan, Hannah Velzen, Marjon van Slegtenhorst, JM Vermeulen, JA Offerhaus, WJ Bai, A de Marvao, N Lahrouchi, L Beekman, JC KarperJH Veldink, E Kayvanpour, A Pantazis, AJ Baksi, N Whiffin, F Mazzarotto, G Sloane, H Suzuki, D Schneider-Luftman, P Elliott, P Richard, F Ader, E Villard, P Lichtner, T Meitinger, MW Tanck, JP Tintelen, A Thain, D McCarty, RA Hegele, JD Roberts, J Amyot, MP Dube, J Cadrin-Tourigny, G Giraldeau, PL L'Allier, P Garceau, JC Tardif, SM Boekholdt, RT Lumbers, FW Asselbergs, PJR Barton, SA Cook, SK Prasad, DP O'Regan, J Velden, KJH Verweij, M Talajic, G Lettre, YM Pinto, B Meder, P Charron, RA de Boer, I Christiaans, Michelle Michels, AA Wilde, H Watkins, PM Matthews, JS Ware, CR Bezzina

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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 language	English
Pages (from-to)	128-134
Number of pages	7
Journal	Nature Genetics
Volume	53
Issue number	2
DOIs	https://doi.org/10.1038/s41588-020-00762-2
Publication status	Published - Feb 2021

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259/

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Tadros, R., Francis, C., Xu, X., Vermeer, A., Harper, AR., Huurman, R., Bisabu, KK., Walsh, R., Hoorntje, ET., te Rijdt, WP., Buchan, RJ., Velzen, H., van Slegtenhorst, M., Vermeulen, JM., Offerhaus, JA., Bai, WJ., de Marvao, A., Lahrouchi, N., Beekman, L., ... Bezzina, CR. (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

@article{23777d6a0c3d4e6cb2e9333700ddfdcb,

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 = "R Tadros and C Francis and X Xu and A Vermeer and AR Harper and Roy Huurman and KK Bisabu and R Walsh and ET Hoorntje and {te Rijdt}, WP and RJ Buchan and Hannah Velzen and {van Slegtenhorst}, Marjon and JM Vermeulen and JA Offerhaus and WJ Bai and {de Marvao}, A and N Lahrouchi and L Beekman and JC Karper and JH Veldink and E Kayvanpour and A Pantazis and AJ Baksi and N Whiffin and F Mazzarotto and G Sloane and H Suzuki and D Schneider-Luftman and P Elliott and P Richard and F Ader and E Villard and P Lichtner and T Meitinger and MW Tanck and JP Tintelen and A Thain and D McCarty and RA Hegele and JD Roberts and J Amyot and MP Dube and J Cadrin-Tourigny and G Giraldeau and PL L'Allier and P Garceau and JC Tardif and SM Boekholdt and RT Lumbers and FW Asselbergs and PJR Barton and SA Cook and SK Prasad and DP O'Regan and J Velden and KJH Verweij and M Talajic and G Lettre and YM Pinto and B Meder and P Charron and {de Boer}, RA and I Christiaans and Michelle Michels and AA Wilde and H Watkins and PM Matthews and JS Ware and CR Bezzina",

year = "2021",

month = feb,

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

language = "English",

volume = "53",

pages = "128--134",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "2",

}

Tadros, R, Francis, C, Xu, X, Vermeer, A, Harper, AR, Huurman, R, Bisabu, KK, Walsh, R, Hoorntje, ET, te Rijdt, WP, Buchan, RJ, Velzen, H, van Slegtenhorst, M, Vermeulen, JM, Offerhaus, JA, Bai, WJ, 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, MW, Tintelen, JP, Thain, A, McCarty, D, Hegele, RA, Roberts, JD, Amyot, J, Dube, MP, Cadrin-Tourigny, J, Giraldeau, G, L'Allier, PL, Garceau, P, Tardif, JC, Boekholdt, SM, Lumbers, RT, Asselbergs, FW, Barton, PJR, Cook, SA, Prasad, SK, O'Regan, DP, Velden, J, Verweij, KJH, Talajic, M, Lettre, G, Pinto, YM, Meder, B, Charron, P, de Boer, RA, Christiaans, I, Michels, M, Wilde, AA, 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, R

AU - Francis, C

AU - Xu, X

AU - Vermeer, A

AU - Harper, AR

AU - Huurman, Roy

AU - Bisabu, KK

AU - Walsh, R

AU - Hoorntje, ET

AU - te Rijdt, WP

AU - Buchan, RJ

AU - Velzen, Hannah

AU - van Slegtenhorst, Marjon

AU - Vermeulen, JM

AU - Offerhaus, JA

AU - Bai, WJ

AU - de Marvao, A

AU - Lahrouchi, N

AU - Beekman, L

AU - Karper, JC

AU - Veldink, JH

AU - Kayvanpour, E

AU - Pantazis, A

AU - Baksi, AJ

AU - Whiffin, N

AU - Mazzarotto, F

AU - Sloane, G

AU - Suzuki, H

AU - Schneider-Luftman, D

AU - Elliott, P

AU - Richard, P

AU - Ader, F

AU - Villard, E

AU - Lichtner, P

AU - Meitinger, T

AU - Tanck, MW

AU - Tintelen, JP

AU - Thain, A

AU - McCarty, D

AU - Hegele, RA

AU - Roberts, JD

AU - Amyot, J

AU - Dube, MP

AU - Cadrin-Tourigny, J

AU - Giraldeau, G

AU - L'Allier, PL

AU - Garceau, P

AU - Tardif, JC

AU - Boekholdt, SM

AU - Lumbers, RT

AU - Asselbergs, FW

AU - Barton, PJR

AU - Cook, SA

AU - Prasad, SK

AU - O'Regan, DP

AU - Velden, J

AU - Verweij, KJH

AU - Talajic, M

AU - Lettre, G

AU - Pinto, YM

AU - Meder, B

AU - Charron, P

AU - de Boer, RA

AU - Christiaans, I

AU - Michels, Michelle

AU - Wilde, AA

AU - Watkins, H

AU - Matthews, PM

AU - Ware, JS

AU - Bezzina, CR

PY - 2021/2

Y1 - 2021/2

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.

UR - http://www.scopus.com/inward/record.url?scp=85099759270&partnerID=8YFLogxK

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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