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, 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
Institute of Cardiovascular Science, University College London, London, UK.
Institute of Health Informatics, University College London, London, UK.
Nat Genet. 2025 Apr;57(4):815-828. doi: 10.1038/s41588-024-02064-3. Epub 2025 Mar 4.
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.
心力衰竭（HF）是全球发病率和死亡率的主要促成因素。虽然根据病因和左心室射血分数定义的不同临床亚型已得到充分认识，但其遗传决定因素仍未得到充分了解。在本研究中，我们报告了一项对190万个体样本进行的HF及其亚型的全基因组关联研究。共有153174人患有HF，其中44012人有非缺血性病因（ni-HF）。在有数据的情况下，根据左心室收缩功能对ni-HF患者的一个子集进行分层，确定了5406名射血分数降低的个体和3841名射血分数保留的个体。我们确定了66个与HF及其亚型相关的基因座，其中37个此前未曾报道。使用功能知情的基因优先级排序方法，我们预测每个已识别基因座的效应基因，并通过全表型关联分析、网络分析和共定位将这些基因映射到病因疾病簇。通过遗传力富集分析，我们强调了心外组织在疾病病因中的作用。然后，我们使用孟德尔随机化研究上游危险因素与HF亚型的差异关联。这些发现扩展了我们对HF病因潜在机制的理解，并可能为未来的预防和治疗方法提供信息。
