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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.* ; Karper, J.C.* ; Veldink, J.H.* ; Kayvanpour, E.* ; Pantazis, A.* ; Baksi, A.J.* ; Whiffin, N.* ; Mazzarotto, F.* ; Sloane, G.* ; Suzuki, H.* ; Schneider-Luftman, D.* ; Elliott, P.* ; Richard, P.* ; Ader, F.* ; Villard, E.* ; Lichtner, P. ; Meitinger, T. ; Tanck, M.W.T.* ; van Tintelen, J.P.* ; Thain, A.* ; McCarty, D.* ; Hegele, R.A.* ; Roberts, J.D.* ; Amyot, J.* ; Dubé, M.P.* ; Cadrin-Tourigny, J.* ; Giraldeau, G.* ; L'Allier, P.L.* ; Garceau, P.* ; Tardif, J.C.* ; Boekholdt, S.M.* ; Lumbers, R.T.* ; Asselbergs, F.W.* ; Barton, P.J.R.* ; Cook, S.A.* ; Prasad, S.K.* ; O'Regan, D.P.* ; van der Velden, J.* ; Verweij, K.J.H.* ; Talajic, M.* ; Lettre, G.* ; Pinto, Y.M.* ; Meder, B.* ; Charron, P.* ; de Boer, R.A.* ; Christiaans, I.* ; Michels, M.* ; Wilde, A.A.M.* ; Watkins, H.* ; Matthews, P.M.* ; Ware, J.S.* ; Bezzina, C.R.*

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

Nat. Genet. 53, 128-134 (2021)
Publ. Version/Full Text DOI
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Mendelian Randomization; Heart; Variants; Contractility; Heritability
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 53, Issue: 2, Pages: 128-134 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants DH | National Institute for Health Research (NIHR)
Hartstichting (Dutch Heart Foundation)
Academy of Medical Sciences
Heart and Stroke Foundation of Canada (Heart and Stroke Foundation)
British Heart Foundation (BHF)