Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
Authors: Albert Henry, Xiaodong Mo, Chris Finan, Mark D Chaffin, Doug Speed, Hanane Issa, Spiros Denaxas, James S Ware, Sean L Zheng, Anders Malarstig, Jasmine Gratton, Isabelle Bond, Carolina Roselli, David Miller, Sandesh Chopade, A Floriaan Schmidt, Erik Abner, Lance Adams, Charlotte Andersson, Krishna G Aragam, Johan Ärnlöv, Geraldine Asselin, Anna Axelsson Raja, Joshua D Backman, Traci M Bartz, Kiran J Biddinger, Mary L Biggs, Heather L Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R Brown, Søren Brunak, Mie Topholm Bruun, Leonard Buckbinder, Henning Bundgaard, David J Carey, Daniel I Chasman, Xing Chen, James P Cook, Tomasz Czuba, Simon de Denus, Abbas Dehghan, Graciela E Delgado, Alexander S Doney, Marcus Dörr, Joseph Dowsett, Samuel C Dudley, Gunnar Engström, Christian Erikstrup, Tõnu Esko, Eric H Farber-Eger, Stephan B Felix, Sarah Finer, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Jonas Ghouse, Vilmantas Giedraitis, Franco Giulianini, John S Gottdiener, Stefan Gross, Daníel F Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Sara Hägg, Christopher M Haggerty, Åsa K Hedman, Anna Helgadottir, Harry Hemingway, Hans Hillege, Craig L Hyde, Bitten Aagaard Jensen, J Wouter Jukema, Isabella Kardys, Ravi Karra, Maryam Kavousi, Jorge R Kizer, Marcus E Kleber, Lars Køber, Andrea Koekemoer, Karoline Kuchenbaecker, Yi-Pin Lai, David Lanfear, Claudia Langenberg, Honghuang Lin, Lars Lind, Cecilia M Lindgren, Peter P Liu, Barry London, Brandon D Lowery, Jian'an Luan, Steven A Lubitz, Patrik Magnusson, Kenneth B Margulies, Nicholas A Marston, Hilary Martin, Winfried März, Olle Melander, Ify R Mordi, Michael P Morley, Andrew P Morris, Alanna C Morrison, Lori Morton, Michael W Nagle, Christopher P Nelson, Alexander Niessner, Teemu Niiranen, Raymond Noordam, Christoph Nowak, Michelle L O'Donoghue, Sisse Rye Ostrowski, Anjali T Owens, Colin N A Palmer, Guillaume Paré, Ole Birger Pedersen, Markus Perola, Marie Pigeyre, Bruce M Psaty, Kenneth M Rice, Paul M Ridker, Simon P R Romaine, Jerome I Rotter, Christian T Ruff, Marc S Sabatine, Neneh Sallah, Veikko Salomaa, Naveed Sattar, Alaa A Shalaby, Akshay Shekhar, Diane T Smelser, Nicholas L Smith, Erik Sørensen, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Per Svensson, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Vinicius Tragante, Stella Trompet, Andre G Uitterlinden, Henrik Ullum, Pim van der Harst, David van Heel, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, Monique Verschuuren, Niek Verweij, Christoffer Rasmus Vissing, Uwe Völker, Adriaan A Voors, Lars Wallentin, Yunzhang Wang, Peter E Weeke, Kerri L Wiggins, L Keoki Williams, Yifan Yang, Bing Yu, Faiez Zannad, Chaoqun Zheng, Folkert W Asselbergs, Thomas P Cappola, Marie-Pierre Dubé, Michael E Dunn, Chim C Lang, Nilesh J Samani, Svati Shah, Ramachandran S Vasan, J Gustav Smith, Hilma Holm, Sonia Shah, Patrick T Ellinor, Aroon D Hingorani, Quinn Wells, R Thomas Lumbers
Journal: Nature Genetics (2025)

Abstract 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.