A1 Refereed original research article in a scientific journal
Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
Authors: Henry Albert; Mo Xiaodong; Finan Chris; Chaffin Mark D.; Speed Doug; Issa Hanane; Denaxas Spiros; Ware James S.; Zheng Sean L.; Malarstig Anders; Gratton Jasmine; Bond Isabelle; Roselli Carolina; Miller David; Chopade Sandesh; Schmidt A. Floriaan; Abner Erik; Adams Lance; Andersson Charlotte; Aragam Krishna G.; Ärnlöv Johan; Asselin Geraldine; Raja Anna Axelsson; Backman Joshua D.; Bartz Traci M.; Biddinger Kiran J.; Biggs Mary L.; Bloom Heather L.; Boersma Eric; Brandimarto Jeffrey; Brown Michael R.; Brunak Søren; Bruun Mie Topholm; Buckbinder Leonard; Bundgaard Henning; Carey David J.; Chasman Daniel I.; Chen Xing; Cook James P.; Czuba Tomasz; de Denus Simon; Dehghan Abbas; Delgado Graciela E.; Doney Alexander S.; Dörr Marcus; Dowsett Joseph; Dudley Samuel C.; Engström Gunnar; Erikstrup Christian; Esko Tõnu; Farber-Eger Eric H.; Felix Stephan B.; Finer Sarah; Ford Ian; Ghanbari Mohsen; Ghasemi Sahar; Ghouse Jonas; Giedraitis Vilmantas; Giulianini Franco; Gottdiener John S.; Gross Stefan; Guðbjartsson Daníel F.; Gui Hongsheng; Gutmann Rebecca; Hägg Sara; Haggerty Christopher M.; Hedman Åsa K.; Helgadottir Anna; Hemingway Harry; Hillege Hans; Hyde Craig L.; Aagaard Jensen Bitten; Jukema J. Wouter; Kardys Isabella; Karra Ravi; Kavousi Maryam; Kizer Jorge R.; Kleber Marcus E.; Køber Lars; Koekemoer Andrea; Kuchenbaecker Karoline; Lai Yi-Pin; Lanfear David; Langenberg Claudia; Lin Honghuang; Lind Lars; Lindgren Cecilia M.; Liu Peter P.; London Barry; Lowery Brandon D.; Luan Jian’an; Lubitz Steven A.; Magnusson Patrik; Margulies Kenneth B.; Marston Nicholas A.; Martin Hilary; März Winfried; Melander Olle; Mordi Ify R.; Morley Michael P.; Morris Andrew P.; Morrison Alanna C.; Morton Lori; Nagle Michael W.; Nelson Christopher P.; Niessner Alexander; Niiranen Teemu; Noordam Raymond; Nowak Christoph; O’Donoghue Michelle L.; Ostrowski Sisse Rye; Owens Anjali T.; Palmer Colin N. A.; Paré Guillaume; Pedersen Ole Birger; Perola Markus; Pigeyre Marie; Psaty Bruce M.; Rice Kenneth M.; Ridker Paul M.; Romaine Simon P. R.; Rotter Jerome I.; Ruff Christian T.; Sabatine Marc S.; Sallah Neneh; Salomaa Veikko; Sattar Naveed; Shalaby Alaa A.; Shekhar Akshay; Smelser Diane T.; Smith Nicholas L.; Sørensen Erik; Srinivasan Sundararajan; Stefansson Kari; Sveinbjörnsson Garðar; Svensson Per; Tammesoo Mari-Liis; Tardif Jean-Claude; Teder-Laving Maris; Teumer Alexander; Thorgeirsson Guðmundur; Thorsteinsdottir Unnur; Torp-Pedersen Christian; Tragante Vinicius; Trompet Stella; Uitterlinden Andre G.; Ullum Henrik; van der Harst Pim; van Heel David; van Setten Jessica; van Vugt Marion; Veluchamy Abirami; Verschuuren Monique; Verweij Niek; Vissing Christoffer Rasmus; Völker Uwe; Voors Adriaan A.; Wallentin Lars; Wang Yunzhang; Weeke Peter E.; Wiggins Kerri L.; Williams L. Keoki; Yang Yifan; Yu Bing; Zannad Faiez; Zheng Chaoqun; Genes & Health Research Team; Estonian Biobank Research Team; DBDS Genomic Consortium; Asselbergs Folkert W.; Cappola Thomas P.; Dubé Marie-Pierre; Dunn Michael E.; Lang Chim C.; Samani Nilesh J.; Shah Svati; Vasan Ramachandran S.; Smith J. Gustav; Holm Hilma; Shah Sonia; Ellinor Patrick T.; Hingorani Aroon D.; Wells Quinn; Lumbers R. Thomas; HERMES Consortium
Publisher: Springer Science and Business Media LLC
Publishing place: BERLIN
Publication year: 2025
Journal: Nature Genetics
Journal name in source: Nature Genetics
Journal acronym: NAT GENET
Volume: 57
First page : 815
Last page: 828
Number of pages: 33
ISSN: 1061-4036
eISSN: 1546-1718
DOI: https://doi.org/10.1038/s41588-024-02064-3
Web address : https://doi.org/10.1038/s41588-024-02064-3
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/491571090
Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.
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Funding information in the publication:
A. Henry was supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship (FS/18/65/34186). R.T.L. and A. Henry were partly supported by a Pfizer Innovative Targets Exploration Network Grant. The project was additionally supported by the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking (grant agreement 116074), the UCL British Heart Foundation Accelerator (AA/18/6/34223), the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR203328) and Health Data Research UK (MR/S003754/1). Analyses using the UKB resource presented in this work were conducted under applications 9922, 15422, 12113, 12505 and 47602. Additional study-level acknowledgements are provided in Supplementary Table 21. We thank all research participants included in this study. The views expressed in this work are those of the authors and not necessarily those of the funders.
