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 and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left v...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Research
2021
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| _version_ | 1826295279858483200 |
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| author | 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 Watkins, H |
| author_facet | 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 Watkins, H |
| author_sort | Tadros, R |
| collection | OXFORD |
| 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 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. |
| first_indexed | 2024-03-07T03:58:35Z |
| format | Journal article |
| id | oxford-uuid:c3ba02f5-a29f-4145-a8b8-d3e86d5db3f0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:58:35Z |
| publishDate | 2021 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:c3ba02f5-a29f-4145-a8b8-d3e86d5db3f02022-03-27T06:18:48ZShared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effectJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c3ba02f5-a29f-4145-a8b8-d3e86d5db3f0EnglishSymplectic ElementsNature Research2021Tadros, RFrancis, CXu, XVermeer, AMCHarper, ARHuurman, RKelu Bisabu, KWalsh, RHoorntje, ETTe Rijdt, WPBuchan, RJvan Velzen, HGvan Slegtenhorst, MAVermeulen, JMOfferhaus, JABai, Wde Marvao, ALahrouchi, NBeekman, LKarper, JCVeldink, JHKayvanpour, EPantazis, ABaksi, AJWhiffin, NMazzarotto, FSloane, GSuzuki, HSchneider-Luftman, DElliott, PRichard, PAder, FVillard, ELichtner, PMeitinger, TTanck, MWTvan Tintelen, JPThain, AMcCarty, DHegele, RARoberts, JDAmyot, JDubé, M-PCadrin-Tourigny, JGiraldeau, GL'Allier, PLGarceau, PTardif, J-CBoekholdt, SMLumbers, RTWatkins, HThe 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. |
| spellingShingle | 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 Watkins, H 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 |
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