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Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

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

Posted 10 Jul 2019
bioRxiv DOI: 10.1101/682013

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 the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent 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.

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