Mapping the aetiological foundations of the heart failure spectrum using human genetics
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 , Axelsson Raja Anna , 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. , Jensen Bitten Aagaard , 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 Mark 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,   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
Published: October 2023

Summary paragraphHeart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-confounding properties of genetic variation to map causal biology underlying the HF phenotypic spectrum, to inform the development of more effective treatments. We report a genetic association analysis in 1.9 million ancestrally diverse individuals, including 153,174 cases of HF; 44,012 of non-ischaemic HF; 5,406 cases of non-ischaemic HF with reduced ejection fraction (HFrEF); and 3,841 cases of non-ischaemic HF with preserved ejection fraction (HFpEF). We identify 66 genetic susceptibility loci across HF subtypes, 37 of which have not previously been reported. We map the aetiologic contribution of risk factor traits and diseases as well as newly identified effector genes for HF, demonstrating differential risk factor effects on disease subtypes. Our findings highlight the importance of extra-cardiac tissues in HF, particularly the kidney and the vasculature in HFpEF. Pathways of cellular senescence and proteostasis are notably uncovered, includingIGFBP7as an effector gene for HFpEF. Using population approaches causally anchored in human genetics, we provide fundamental new insights into the aetiology of heart failure subtypes that may inform new approaches to prevention and treatment.