Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure
Authors: Shah Sonia , Henry Albert , Roselli Carolina , Lin Honghuang , Sveinbjörnsson Garðar , Fatemifar Ghazaleh , Hedman Åsa K. , Wilk Jemma B. , Morley Michael P. , Chaffin Mark D. , Helgadottir Anna , Verweij Niek , Dehghan Abbas , Almgren Peter , Andersson Charlotte , Aragam Krishna G. , Ärnlöv Johan , Backman Joshua D. , Biggs Mary L. , Bloom Heather L. , Brandimarto Jeffrey ,   Broad AF Investigators, Brown Michael R. , Buckbinder Leonard , Carey David J. ,   Regeneron Genetics Center, Chasman Daniel I. , Chen Xing , Chen Xu , Chung Jonathan , Chutkow William , Cook James P. , Delgado Graciela E. , Denaxas Spiros , Doney Alexander S. , Dörr Marcus , Dudley Samuel C. , Dunn Michael E. ,   EchoGen Consortium, Engström Gunnar , Esko Tõnu , Felix Stephan B. , Finan Chris , Ford Ian , Ghanbari Mohsen , Ghasemi Sahar , Giedraitis Vilmantas , Giulianini Franco , Gottdiener John S. , Gross Stefan , Guðbjartsson Daníel F. , Gutmann Rebecca , Haggerty Christopher M. , van der Harst Pim , Hyde Craig L. , Ingelsson Erik , Jukema J. Wouter , Kavousi Maryam , Khaw Kay-Tee , Kleber Marcus E. , Køber Lars , Koekemoer Andrea , Langenberg Claudia , Lind Lars , Lindgren Cecilia M. , London Barry , Lotta Luca A. , Lovering Ruth C. , Luan Jian’an , Magnusson Patrik , Mahajan Anubha , Margulies Kenneth B. , März Winfried , Melander Olle , Mordi Ify R. , Morgan Thomas , Morris Andrew D. , Morris Andrew P. , Morrison Alanna C. , Nagle Michael W. , Nelson Christopher P. , Niessner Alexander , Niiranen Teemu , O’Donoghue Michelle L. , Owens Anjali T. , Palmer Colin N. A. , Parry Helen M. , Perola Markus , Portilla-Fernandez Eliana , Psaty Bruce M. , Rice Kenneth M. , Ridker Paul M. , Romaine Simon P. R. , Rotter Jerome I. , Salo Perttu , Salomaa Veikko , van Setten Jessica , Shalaby Alaa A. , Smelser Diane T. , Smith Nicholas L. , Stender Steen , Stott David J. , Svensson Per , Tammesoo Mari-Liis , Taylor Kent D. , Teder-Laving Maris , Teumer Alexander , Thorgeirsson Guðmundur , Thorsteinsdottir Unnur , Torp-Pedersen Christian , Trompet Stella , Tyl Benoit , Uitterlinden Andre G. , Veluchamy Abirami , Völker Uwe , Voors Adriaan A. , Wang Xiaosong , Wareham Nicholas J. , Waterworth Dawn , Weeke Peter E. , Weiss Raul , Wiggins Kerri L. , Xing Heming , Yerges-Armstrong Laura M. , Yu Bing , Zannad Faiez , Zhao Jing Hua , Hemingway Harry , Samani Nilesh J. , McMurray John J.V. , Yang Jian , Visscher Peter M. , Newton-Cheh Christopher , Malarstig Anders , Holm Hilma , Lubitz Steven A. , Sattar Naveed , Holmes Michael V. , Cappola Thomas P. , Asselbergs Folkert , Hingorani Aroon D. , Kuchenbaecker Karoline , Ellinor Patrick T. , Lang Chim C. , Stefansson Kari , Smith J. Gustav , Vasan Ramachandran S. , Swerdlow Daniel I. , Lumbers R. Thomas 
Published: July 2019

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide1. 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 unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.