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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-13690-5

2041-1723

Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark Chaffin, Anna Helgadóttir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William A. Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alex S. F. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, 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 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 K. E. Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify Mordi, Thomas M. Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali Owens, Nicholette D. Palmer, Helen Parry, Markus Perola, Eliana Portilla-Fernández, Bruce M. Psaty, Goncalo Abecasis, Joshua Backman, Xiaodong Bai, Suganthi Balasubramanian, Nilanjana Banerjee, Aris Baras, Leland Barnard, Christina Beechert, Andrew Blumenfeld, Michael Cantor, Yating Chai, Jonathan Chung, Giovanni Coppola, Amy Damask, Frederick E. Dewey, Aris Economides, Gisu Eom, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Lauren Gurski, Paloma M. Guzzardo, Lukas Habegger, Young Hahn, Alicia Hawes, Cristopher V. Van Hout, Marcus B. Jones, Shareef Khalid, Michael Lattari, Alexander Li, Nan Lin, Daren Liu, Alexander Lopez, Kia Manoochehri, Jonathan Marchini, Anthony Marcketta, Evan K. Maxwell, Shane McCarthy, Lyndon J. Mitnaul, Colm O’Dushlaine, John D. Overton, Maria Sotiropoulos Padilla, Charles Paulding, John S. Penn, Manasi Pradhan, Jeffrey G. Reid, Thomas D. Schleicher, Claudia Schurmann, Alan R. Shuldiner, Jeffrey C. Staples, Dylan Sun, Karina Toledo, Ricardo H. Ulloa, Louis Widom, Sarah E. Wolf, Ashish Yadav, Bin Ye, Kenneth Rice, Paul M. Ridker, Simon P.R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari‐Liis Tammesoo, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Þorgeirsson, Unnur Þorsteinsdóttir, Christian Torp‐Pedersen, Stella Trompet, Benoît Tyl, André G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faı̈ez Zannad, Jing Zhao, Harry Hemingway, Nilesh J. Samani, John J.V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton‐Cheh, Anders Mälarstig, 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, Kári Stéfansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, R. Thomas Lumbers,

Genetics and Neurodevelopmental Disorders

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.