Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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Published:2020-01-09
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Shah SoniaORCID, , Henry AlbertORCID, Roselli CarolinaORCID, Lin HonghuangORCID, Sveinbjörnsson Garðar, Fatemifar Ghazaleh, Hedman Åsa K., Wilk Jemma B., Morley Michael P., Chaffin Mark D.ORCID, Helgadottir AnnaORCID, Verweij NiekORCID, Dehghan Abbas, Almgren PeterORCID, 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 XuORCID, 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 MohsenORCID, Ghasemi Sahar, Giedraitis VilmantasORCID, Giulianini Franco, Gottdiener John S., Gross StefanORCID, Guðbjartsson Daníel F.ORCID, Gutmann Rebecca, Haggerty Christopher M., van der Harst Pim, Hyde Craig L.ORCID, Ingelsson ErikORCID, Jukema J. WouterORCID, Kavousi Maryam, Khaw Kay-Tee, Kleber Marcus E.ORCID, Køber Lars, Koekemoer AndreaORCID, Langenberg ClaudiaORCID, Lind Lars, Lindgren Cecilia M.ORCID, London Barry, Lotta Luca A., Lovering Ruth C.ORCID, Luan Jian’anORCID, Magnusson PatrikORCID, Mahajan AnubhaORCID, Margulies Kenneth B., März Winfried, Melander Olle, Mordi Ify R.ORCID, Morgan Thomas, Morris Andrew D.ORCID, Morris Andrew P., Morrison Alanna C., Nagle Michael W.ORCID, Nelson Christopher P.ORCID, Niessner Alexander, Niiranen Teemu, O’Donoghue Michelle L., Owens Anjali T., Palmer Colin N. A.ORCID, Parry Helen M., Perola Markus, Portilla-Fernandez Eliana, Psaty Bruce M., Rice Kenneth M.ORCID, Ridker Paul M., Romaine Simon P. R., Rotter Jerome I.ORCID, Salo Perttu, Salomaa VeikkoORCID, van Setten JessicaORCID, Shalaby Alaa A., Smelser Diane T., Smith Nicholas L., Stender Steen, Stott David J., Svensson PerORCID, Tammesoo Mari-Liis, Taylor Kent D.ORCID, Teder-Laving MarisORCID, Teumer AlexanderORCID, Thorgeirsson Guðmundur, Thorsteinsdottir Unnur, Torp-Pedersen Christian, Trompet Stella, Tyl BenoitORCID, Uitterlinden Andre G.ORCID, Veluchamy Abirami, Völker UweORCID, Voors Adriaan A., Wang Xiaosong, Wareham Nicholas J., Waterworth Dawn, Weeke Peter E., Weiss Raul, Wiggins Kerri L.ORCID, Xing Heming, Yerges-Armstrong Laura M., Yu Bing, Zannad Faiez, Zhao Jing Hua, Hemingway HarryORCID, Samani Nilesh J., McMurray John J. V., Yang JianORCID, Visscher Peter M.ORCID, Newton-Cheh Christopher, Malarstig Anders, Holm Hilma, Lubitz Steven A.ORCID, Sattar NaveedORCID, Holmes Michael V., Cappola Thomas P.ORCID, Asselbergs Folkert W.ORCID, Hingorani Aroon D., Kuchenbaecker KarolineORCID, Ellinor Patrick T.ORCID, Lang Chim C., Stefansson Kari, Smith J. Gustav, Vasan Ramachandran S.ORCID, Swerdlow Daniel I., Lumbers R. ThomasORCID
Abstract
AbstractHeart 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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