Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
Sean L. Zheng(Guy's and St Thomas' NHS Foundation Trust), Albert Henry(University College London), Douglas Cannie(St Bartholomew's Hospital), Michael Lee(Imperial College London), D.J. Miller(University College London), Kathryn A. McGurk(Broad Institute), Isabelle Bond(University College London), Xiao Yun Xu(Imperial College London), Hanane Issa(University College London), Catherine Francis(Guy's and St Thomas' NHS Foundation Trust), Antonio de Marvao(Guy's and St Thomas' NHS Foundation Trust), Pantazis Theotokis(Guy's and St Thomas' NHS Foundation Trust), Rachel Buchan(Guy's and St Thomas' NHS Foundation Trust), Doug Speed(Aarhus University), Erik Abner(University of Tartu), Lance Adams(Geisinger Health System), Krishna G. Aragam(Broad Institute), Johan Ärnlöv(Dalarna University), Anna Axelsson Raja(Copenhagen University Hospital), Joshua Backman(Regeneron (United States)), John Baksi(Guy's and St Thomas' NHS Foundation Trust), Paul J.R. Barton(Guy's and St Thomas' NHS Foundation Trust), Kiran J. Biddinger(Broad Institute), Eric Boersma(Erasmus MC), Jeffrey Brandimarto(University of Pennsylvania), Søren Brunak(University of Copenhagen), Henning Bundgaard(Copenhagen University Hospital), David J. Carey(Geisinger Medical Center), Philippe Charron(Sorbonne Université), James P. Cook(University of Liverpool), Stuart A. Cook(Guy's and St Thomas' NHS Foundation Trust), Spiros Denaxas(National Institute for Health and Care Research), Jean‐François Deleuze(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Alex S. F. Doney(University of Dundee), Perry Elliott(St Bartholomew's Hospital), Christian Erikstrup(Aarhus University Hospital), Tõnu Esko(Broad Institute), Eric Farber‐Eger(Vanderbilt University Medical Center), Chris Finan(University College London), Sophie Garnier(Biologie des maladies cardiovasculaires), Jonas Ghouse(Copenhagen University Hospital), Vilmantas Giedraitis, Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Christopher M. Haggerty(Geisinger Medical Center), Brian P. Halliday(Guy's and St Thomas' NHS Foundation Trust), Anna Helgadóttir(deCODE Genetics (Iceland)), Harry Hemingway(Health Data Research UK), Hans L. Hillege(University Medical Center Groningen), Isabella Kardys(Erasmus MC), Lars Lind(Uppsala University), Cecilia M. Lindgren(Broad Institute), Brandon D. Lowery(Vanderbilt University Medical Center), Charlotte Manisty(St Bartholomew's Hospital), Kenneth B. Margulies(University of Copenhagen), James Moon(St Bartholomew's Hospital), Ify Mordi(University of Dundee), Michael P. Morley(University of Copenhagen), Andrew D. Morris(University of Manchester), Andrew P. Morris(Centre for Human Genetics), Lori Morton(Regeneron (United States)), Mahdad Noursadeghi(Regeneron (United States)), Sisse Rye Ostrowski(University of Copenhagen), Anjali Owens(University of Pennsylvania), Colin N. A. Palmer(University of Dundee), Antonis Pantazis(Guy's and St Thomas' NHS Foundation Trust), Ole B. V. Pedersen(University of Copenhagen), Sanjay Prasad(Regeneron (United States)), Akshay Shekhar(Geisinger Medical Center), Diane T. Smelser(Geisinger Medical Center), Sundararajan Srinivasan(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Garðar Sveinbjörnsson(deCODE Genetics (Iceland)), Petros Syrris(University College London), Mari‐Liis Tammesoo(Guy's and St Thomas' NHS Foundation Trust), Upasana Tayal(Guy's and St Thomas' NHS Foundation Trust), Maris Teder‐Laving(deCODE Genetics (Iceland)), Guðmundur Thorgeirsson(deCODE Genetics (Iceland)), Unnur Thorsteinsdottir(deCODE Genetics (Iceland)), Vinicius Tragante(deCODE Genetics (Iceland)), David‐Alexandre Trégouët(St Bartholomew's Hospital), Thomas A. Treibel(St Bartholomew's Hospital), Henrik Ullum(Statens Serum Institut), Ana M. Valdes(University of Nottingham), Jessica van Setten(University of Nottingham), Marion van Vugt(University of Copenhagen), Abirami Veluchamy(University of Dundee), W. M. Monique Verschuren(University Medical Center Utrecht), Eric Villard(Biologie des maladies cardiovasculaires), Yifan Yang(Regeneron (United States)), COVIDsortium(Copenhagen University Hospital), Mahdad Noursadeghi(deCODE Genetics (Iceland)), Ole B. V. Pedersen(University of Copenhagen), Kāri Stefánsson(deCODE Genetics (Iceland)), Unnur Thorsteinsdottir(deCODE Genetics (Iceland)), Henrik Ullum(Statens Serum Institut), Folkert W. Asselbergs(Montreal Heart Institute), Antonio de Marvao(Guy's and St Thomas' NHS Foundation Trust), Marie‐Pierre Dubé(Montreal Heart Institute), Michael E. Dunn(Regeneron (United States)), Patrick T. Ellinor(Broad Institute), Sophie Garnier(University of Manchester), Chim C. Lang(University of Dundee), Andrew P. Morris(University of Copenhagen), Lori Morton(Regeneron (United States)), Colin N. A. Palmer(University of Dundee), Nilesh J. Samani(University of Leicester), Svati H. Shah(Lund University), Akshay Shekhar(University of Copenhagen), J. G. Smith(deCODE Genetics (Iceland)), Sundarajan Srinivasan(University of Dundee), Guðmundur Thorgeirsson(deCODE Genetics (Iceland)), Ramachandran S. Vasan(Boston University), Jessica van Setten(University of Dundee), Marion van Vugt(University Medical Center Utrecht), Abirami Veluchamy(University of Dundee), W. M. Monique Verschuuren(University Medical Center Utrecht), Eric Villard(National Institute for Health and Care Research), Quinn S. Wells(Vanderbilt University), Folkert W. Asselbergs(Montreal Heart Institute), Thomas P. Cappola(Regeneron (United States)), Marie‐Pierre Dubé(Montreal Heart Institute), Michael E. Dunn(Regeneron (United States)), Patrick T. Ellinor(Broad Institute), Aroon D. Hingorani(Massachusetts General Hospital), Chim C. Lang(University of Dundee), Nilesh J. Samani(University of Leicester), Svati H. Shah(Lund University), J. G. Smith(Lund University), Ramachandran S. Vasan(Boston University), Declan P. O’Regan(Imperial College London), Hilma Hólm(deCODE Genetics (Iceland)), Michela Noseda(Broad Institute), Quinn S. Wells(Vanderbilt University), James S. Ware(Broad Institute), R Thomas Lumbers(British Heart Foundation)
Cited by 53Open Access
Abstract
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.
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