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; Kelu Bisabu, Ken; 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.
(2021) Nature Genetics, volume 53, issue 2, pp. 128 - 134
(Article)
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
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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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Keywords: Genetics
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: Blackburn Chair in Cardiovascular Research, and has received operating grants from the Canadian Institutes of Health Research (Foundation award) and the Heart and Stroke Foundation of Canada (G-18-0022147). M.-P.D. holds a Canada Research Chair in Precision Medicine Data Analysis. J.-C.T. holds the Canada Research Chair in personalized medicine and the University of Montreal endowed research chair in atherosclerosis and is the principal investigator of the Montreal Heart Institute André and France Desmarais hospital cohort funded by the Montreal Heart Institute Foundation. R.T.L. is supported by a UK Research and Innovation Rutherford Fellowship. F.W.A. is supported by the UCL Hospitals NIHR Biomedical Research Centre. F.W.A. and P.C. received support from European Union’s Horizon 2020 research and innovation program under the ERA-NET Co-fund action no. 680969 (ERA-CVD DETECTIN-HF), jointly funded by the Dutch Heart Foundation (2016T096) and Netherlands Organization for Health Research and Development (ZonMw). P.J.R.B. and J.S.W. are supported by a Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, UK (HICF-R6–373). D.P.O’R. is funded by the Medical Research Council, NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London, and a British Heart Foundation Program Grant (RG/19/6/34387). K.J.H.V. receives support from the Foundation Volksbond Rotterdam. M.T. receives support from the Monat foundation. G.L. is funded by the Montreal Heart Institute Foundation, the J. C. Edwards Foundation and the Canada Research Chair Program. B.M. received support from DZHK, the German Ministry of Education and Research (CaRNAtion), Informatics for Life (Klaus Tschira Foundation) and the European Union (FP7 BestAgeing), and was supported by an excellence fellowship of the Else Kröner Fresenius Foundation. P.C. received funding from PROMEX charitable foundation. H.W. has received support from the Wellcome Trust core award (090532/Z/09/Z), the BHF Centre of Research Excellence, Oxford (RE/13/1/30181), the NIHR Oxford Biomedical Research Centre and a National Heart, Lung and Blood Institute grant (U01HL117006-01A1). P.M.M. acknowledges generous personal and research support from the Edmond J. Safra Foundation and Lily Safra, an NIHR Senior Investigator Award and the UK Dementia Research Institute. J.S.W. was supported by Wellcome Trust (107469/Z/15/Z); British Heart Foundation (SP/17/11/32885; RE/18/4/34215); Medical Research Council (UK); NIHR Royal Brompton Cardiovascular Biomedical Research Unit; NIHR Imperial College Biomedical Research Centre. C.R.B. acknowledges support from the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and the Leducq Foundation (project 17CVD02). This research has been conducted in part using the UK Biobank Resource under Application Number 18454, and the Genotype-Tissue Expression (GTEx) Project supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neorological Disorders and Stroke (NINDS). This study was supported by a kind donation from family and friends of Jean-Paul Balkestein who died at 32 years of age from hypertrophic cardiomyopathy. Funding Information: R.T. received funding from the Canadian Heart Rhythm Society (George Mines Award), the European Society of Cardiology (Research fellowship grant), the Canadian Institutes of Health Research (funding reference number 169063) and the Fonds de Recherche du Québec—Santé (reference number 135055). R.T. and J.C.-T. received support from the Philippa and Marvin Carsley Cardiology Chair. C.F. received funding from a British Heart Foundation Clinical Research Training Fellowship FS/15/81/31817. X.X. is currently a postdoctoral scientist funded by the Medical Research Council London Institute of Medical Sciences. A.R.H. received support from the Medical Research Council Doctoral Training Partnership. R.W. received support from an Amsterdam Cardiovascular Sciences fellowship. E.T.H. and W.P.t.R. received support from the Young Talent Program of the Dutch Heart Foundation (CVON PREDICT 2012-10). W.P.t.R. is supported by a postdoctoral fellowship CURE-PLaN (Netherlands Heart Institute) from the Leducq Foundation. J.A.O. received support from the Amsterdam UMC’s PhD scholarship. A.d.M. received support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London; the Medical Research Council, UK; the Academy of Medical Sciences (SGL015/1006) and a Mason Medical Research Trust grant. J.H.V. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant no 772376 - EScORIAL). E.K. received support from the German Center for Cardiovascular Research (DZHK) Rotation Grant. F.M. is supported by a postdoctoral research fellowship from the University of Florence and by the European Union Horizon 2020 framework programme (SILICOFCM, GA 777204). H.S. received support from grants from the Japan Society for the Promotion of Science (18K15410). D.S.-L. received support from UK Med-Bio. P.R. received support from the Fédération Française de Cardiologie. P.R. and F.A. were supported by Ligue contre la cardiomyopathie. E.V. and P.C. received support from the CONNY-MAEVA charitable foundation and GenMed LABEX. The study was supported by the Dutch Heart Foundation Netherlands Cardiovascular Research Initiative (CVON; PREDICT2 2018-30 to J.P.v.T., A.A.M.W. and C.R.B.; eDETECT 2015-12 to J.P.v.T. and I.C.; DOSIS 2014-40 to J.P.v.T., F.W.A., J.v.d.V., R.A.d.B. and M.M.; PRIME to Y.M.P.; and DOLPHIN-GENESIS 2017-10 to I.C.). R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics and the Martha G. Funding Information: M.-P.D. is author on a patent pertaining to pharmacogenomics-guided CETP inhibition (US20170233812A1), has a minor equity interest in DalCor and has received honoraria from Dalcor and Servier and research support (access to samples and data) from AstraZeneca, Pfizer, Servier, Sanofi and GlaxoSmithKline. J.-C.T. has received research grants from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Sanofi and Servier; honoraria from AstraZeneca, DalCor, HLS, Sanofi and Servier; holds minor equity interest in DalCor; and is an author of a patent on pharmacogenomics-guided CETP inhibition (US20170233812A1). B.M. has received research funding from Siemens Healtheneers, Daiichi Sankyo. The UMCG, which employs R.A.d.B., has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk and Roche. R.A.d.B. received speaker fees from Abbott, AstraZeneca, Novartis and Roche. HW is a consultant for Cytokinetics. P.M.M. receives an honorarium as Chair of the UKRI Medical Research Council Neuroscience and Mental Health Board. He acknowledges consultancy fees from Adelphi Communications, MedScape, Neurodiem, Nodthera, Biogen, Celgene and Roche. He has received speakers’ honoraria from Celgene, Biogen, Novartis and Roche, and has received research or educational funds from Biogen, GlaxoSmithKline and Novartis. He is paid as a member of the Scientific Advisory Board for Ipsen Pharmaceuticals. J.S.W. has received research support and consultancy fees from Myokardia, Inc. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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