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

Journal article


Shah, Sonia, Albert Henry, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G., Ärnlöv, Johan, Backman, Joshua D., Biggs, Mary L., ... Lumbers, R. Thomas. (2020). Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications. 11(1), pp. 1-12. https://doi.org/10.1038/s41467-019-13690-5
AuthorsShah, Sonia, Albert Henry, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, 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, Chatwick, 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, Tee Khaw, Kay, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Jian’an Luan, 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, 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, Andre G. Uitterlinden, Veluchamy, Abirami, Uwe Völker, Adriaan A. Voors, Wang, Xiaosong, Nicholas J. Wareham, Waterworth, Dawn, Weeke, Peter E., Raul Weiss, 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, C., Malarstig, Anders, Holm, Hilma, Lubitz, Steven A., Sattar, Naveed, Holmes, Michael V., Cappola, Thomas P., Asselbergs, Folkert W., Hingorani, Aroon D., Kuchenbaecker, Karoline B., Ellinor, Patrick T., Lang, Chim C., Stefansson, Kari, Gustav, J. Smith, Vasan, Ramachandran S., Swerdlow, Daniel I. and Lumbers, R. Thomas
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.

Year2020
JournalNature Communications
Journal citation11 (1), pp. 1-12
PublisherNature Publishing Group
ISSN2041-1723
Digital Object Identifier (DOI)https://doi.org/10.1038/s41467-019-13690-5
Scopus EID2-s2.0-85077697294
Open accessPublished as ‘gold’ (paid) open access
Page range1-12
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online09 Jan 2020
Publication process dates
Accepted18 Nov 2019
Deposited01 Nov 2022
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