Genome-wide association and Mendelian randomisation analysis provide insights into the 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 , Brown Michael R. , Buckbinder Leonard , Carey David J. , 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. , 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. ,   Regeneron Genetics Center, Abecasis Goncalo , Backman Joshua , Bai Xiaodong , Balasubramanian Suganthi , Banerjee Nilanjana , Baras Aris , Barnard Leland , Beechert Christina , Blumenfeld Andrew , Cantor Michael , Chai Yating , Chung Jonathan , Coppola Giovanni , Damask Amy , Dewey Frederick , Economides Aris , Eom Gisu , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Gurski Lauren , Guzzardo Paloma M. , Habegger Lukas , Hahn Young , Hawes Alicia , van Hout Cristopher , Jones Marcus B. , Khalid Shareef , Lattari Michael , Li Alexander , Lin Nan , Liu Daren , Lopez Alexander , Manoochehri Kia , Marchini Jonathan , Marcketta Anthony , Maxwell Evan K. , McCarthy Shane , Mitnaul Lyndon J. , O’Dushlaine Colm , Overton John D. , Padilla Maria Sotiropoulos , Paulding Charles , Penn John , Pradhan Manasi , Reid Jeffrey G. , Schleicher Thomas D. , Schurmann Claudia , Shuldiner Alan , Staples Jeffrey C. , Sun Dylan , Toledo Karina , Ulloa Ricardo H. , Widom Louis , Wolf Sarah E. , Yadav Ashish , Ye Bin , 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 W. , 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: January 2020

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.