Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
Sonia Shah(The University of Queensland), Albert Henry(University College London), Carolina Roselli(Broad Institute), Honghuang Lin(Boston University), Garðar Sveinbjörnsson(deCODE Genetics (Iceland)), Ghazaleh Fatemifar(University of London), Åsa K. Hedman(Karolinska Institutet), Jemma B. Wilk(Pfizer (United States)), Michael P. Morley(University of Pennsylvania), Mark Chaffin(Broad Institute), Anna Helgadóttir(deCODE Genetics (Iceland)), Niek Verweij(Broad Institute), Abbas Dehghan(Imperial College London), Peter Almgren(Lund University), Charlotte Andersson(Herlev Hospital), Krishna G. Aragam(Broad Institute), Johan Ärnlöv(Dalarna University), Joshua Backman(Regeneron (United States)), Mary L. Biggs(University of Washington), Heather L. Bloom(Emory University), Jeffrey Brandimarto(University of Pennsylvania), Michael R. Brown, Leonard Buckbinder(Pfizer (United States)), David J. Carey(Geisinger Medical Center), Daniel I. Chasman(Brigham and Women's Hospital), Xing Chen(Pfizer (United States)), Xu Chen(Pfizer (United States)), Jonathan Chung(Regeneron (United States)), William A. Chutkow(Novartis (United States)), James P. Cook(University of Liverpool), Graciela E. Delgado(Heidelberg University), Spiros Denaxas(University of London), Alex S. F. Doney(University of Dundee), Marcus Dörr(Universitätsmedizin Greifswald), Samuel C. Dudley(University of Minnesota), Michael E. Dunn(Regeneron (United States)), Gunnar Engström(Lund University), Tõnu Esko(Broad Institute), Stephan B. Felix(Universitätsmedizin Greifswald), Chris Finan(University College London), Ian Ford(University of Glasgow), Mohsen Ghanbari(Erasmus MC), Sahar Ghasemi(Universitätsmedizin Greifswald), Vilmantas Giedraitis(Uppsala University), Franco Giulianini(Brigham and Women's Hospital), John S. Gottdiener(University of Maryland, Baltimore), Stefan Groß(Universitätsmedizin Greifswald), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Rebecca Gutmann(University of Iowa), Christopher M. Haggerty(Geisinger Medical Center), Pim van der Harst(University Medical Center Groningen), Craig Hyde(Pfizer (United States)), Erik Ingelsson(Uppsala University), J. Wouter Jukema(Leiden University Medical Center), Maryam Kavousi(Erasmus MC), Kay‐Tee Khaw(University of Cambridge), Marcus E. Kleber(Heidelberg University), Lars Køber(Copenhagen University Hospital), Andrea Koekemoer(University of Leicester), Claudia Langenberg(University of Cambridge), Lars Lind(Uppsala University), Cecilia M. Lindgren(Broad Institute), Barry London(University of Iowa), Luca A. Lotta(University of Cambridge), Ruth C. Lovering(University College London), Jian’an Luan(University of Cambridge), Patrik K. E. Magnusson(Karolinska Institutet), Anubha Mahajan(Centre for Human Genetics), Kenneth B. Margulies(University of Pennsylvania), Winfried März(University of Liverpool), Olle Melander(Lund University), Ify Mordi(University of Dundee), Thomas M. Morgan(Vanderbilt University), Andrew D. Morris(Centre for Human Genetics), Andrew P. Morris(Centre for Human Genetics), Alanna C. Morrison, Michael W. Nagle(Pfizer (United States)), Christopher P. Nelson(University of Leicester), Alexander Niessner(Medical University of Vienna), Teemu Niiranen(University of Turku), Michelle L. O’Donoghue(Brigham and Women's Hospital), Anjali Owens(University of Pennsylvania), Colin N. A. Palmer(University of Dundee), Helen Parry(University of Dundee), Markus Perola(Finnish Institute for Health and Welfare), Eliana Portilla-Fernández(Erasmus MC), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), Goncalo Abecasis(Regeneron (United States)), Joshua Backman(Regeneron (United States)), Xiaodong Bai(Regeneron (United States)), Suganthi Balasubramanian(Regeneron (United States)), Nilanjana Banerjee(Regeneron (United States)), Aris Baras(Regeneron (United States)), Leland Barnard(Regeneron (United States)), Christina Beechert(Regeneron (United States)), Andrew Blumenfeld(Regeneron (United States)), Michael Cantor(Regeneron (United States)), Yating Chai(Regeneron (United States)), Jonathan Chung(Regeneron (United States)), Giovanni Coppola(Regeneron (United States)), Amy Damask(Regeneron (United States)), Frederick E. Dewey(Regeneron (United States)), Aris Economides(Regeneron (United States)), Gisu Eom(Regeneron (United States)), Caitlin Forsythe(Regeneron (United States)), Erin D. Fuller(Regeneron (United States)), Zhenhua Gu(Regeneron (United States)), Lauren Gurski(Regeneron (United States)), Paloma M. Guzzardo(Regeneron (United States)), Lukas Habegger(Regeneron (United States)), Young Hahn(Regeneron (United States)), Alicia Hawes(Regeneron (United States)), Cristopher V. Van Hout(Regeneron (United States)), Marcus B. Jones(Regeneron (United States)), Shareef Khalid(Regeneron (United States)), Michael Lattari(Regeneron (United States)), Alexander Li(Regeneron (United States)), Nan Lin(Regeneron (United States)), Daren Liu(Regeneron (United States)), Alexander Lopez(Regeneron (United States)), Kia Manoochehri(Regeneron (United States)), Jonathan Marchini(Regeneron (United States)), Anthony Marcketta(Regeneron (United States)), Evan K. Maxwell(Regeneron (United States)), Shane McCarthy(Regeneron (United States)), Lyndon J. Mitnaul(Regeneron (United States)), Colm O’Dushlaine(Regeneron (United States)), John D. Overton(Regeneron (United States)), Maria Sotiropoulos Padilla(Regeneron (United States)), Charles Paulding(Regeneron (United States)), John S. Penn(Regeneron (United States)), Manasi Pradhan(Regeneron (United States)), Jeffrey G. Reid(Regeneron (United States)), Thomas D. Schleicher(Regeneron (United States)), Claudia Schurmann(Regeneron (United States)), Alan R. Shuldiner(Regeneron (United States)), Jeffrey C. Staples(Regeneron (United States)), Dylan Sun(Regeneron (United States)), Karina Toledo(Regeneron (United States)), Ricardo H. Ulloa(Regeneron (United States)), Louis Widom(Regeneron (United States)), Sarah E. Wolf(Regeneron (United States)), Ashish Yadav(Regeneron (United States)), Bin Ye(Regeneron (United States)), Kenneth Rice(University of Washington), Paul M. Ridker(Brigham and Women's Hospital), Simon P.R. Romaine(University of Leicester), Jerome I. Rotter(The Lundquist Institute), Perttu Salo(Finnish Institute for Health and Welfare), Veikko Salomaa(Finnish Institute for Health and Welfare), Jessica van Setten(Utrecht University), Alaa Shalaby(University of Pittsburgh Medical Center), Diane T. Smelser(Geisinger Medical Center), Nicholas L. Smith(Kaiser Permanente Washington Health Research Institute), Steen Stender(Copenhagen University Hospital), David J. Stott(University of Glasgow), Per Svensson(Karolinska Institutet), Mari‐Liis Tammesoo(University of Tartu), Kent D. Taylor(UCLA Medical Center), Maris Teder‐Laving(University of Tartu), Alexander Teumer(Universitätsmedizin Greifswald), Guðmundur Þorgeirsson(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Christian Torp‐Pedersen(Aalborg University Hospital), Stella Trompet(Leiden University Medical Center), Benoît Tyl(Servier (France)), André G. Uitterlinden(Erasmus MC), Abirami Veluchamy(University of Dundee), Uwe Völker(Universitätsmedizin Greifswald), Adriaan A. Voors(Boston University), Xiaosong Wang(Novartis (United States)), Nicholas J. Wareham(University of Cambridge), Dawn Waterworth(GlaxoSmithKline (United States)), Peter Weeke(Copenhagen University Hospital), Raul Weiss(The Ohio State University Wexner Medical Center), Kerri L. Wiggins(University of Washington), Heming Xing(Novartis (United States)), Laura M. Yerges-Armstrong(GlaxoSmithKline (United States)), Bing Yu, Faı̈ez Zannad(Inserm), Jing Zhao(University of Cambridge), Harry Hemingway(University of London), Nilesh J. Samani(University of Leicester), John J.V. McMurray(University of Glasgow), Jian Yang(The University of Queensland), Peter M. Visscher(The University of Queensland), Christopher Newton‐Cheh(Broad Institute), Anders Mälarstig(Pfizer (United States)), Hilma Holm(deCODE Genetics (Iceland)), Steven A. Lubitz(Broad Institute), Naveed Sattar(University of Glasgow), Michael V. Holmes(National Institute for Health and Care Research), Thomas P. Cappola(University of Pennsylvania), Folkert W. Asselbergs(Utrecht University), Aroon D. Hingorani(University College London), Karoline Kuchenbaecker(University College London), Patrick T. Ellinor(Broad Institute), Chim C. Lang(University of Dundee), Kāri Stefánsson(deCODE Genetics (Iceland)), J. Gustav Smith(Broad Institute), Ramachandran S. Vasan(Boston University), Daniel I. Swerdlow(University College London), R Thomas Lumbers(St Bartholomew's Hospital)
Cited by 920Open Access
Abstract
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.