Global genomics in over 4 million individuals prioritizes therapeutic targets for heart failure and its subtypes
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality. We conducted multi-ancestry genome-wide association studies of 345,687 HF cases (4,468,166 individuals), and 47,192 and 46,934 cases of HF with preserved (HFpEF) and reduced ejection fraction (HFrEF), respectively, integrating plasma proteomics and multi-tissue transcriptomics to identify druggable targets. Across HF, HFrEF, and HFpEF, we identified 383 loci (166 novel) and 568 genes (375 novel). Eleven novel genes are targets of approved or investigational cardiovascular therapies, supporting indication expansion of aldosterone synthase inhibitors ( CYP11B2 ) and type-II activin receptor antagonists ( ACVR2A ) to HF. Six cardiomyopathy genes were novel for HF and associated with cardiac structure and function. We identified nearly 100 genes involved in food intake and energy expenditure; metabolism of fatty acids, glucose, and branched-chain amino acids; and mitochondrial proteome, sustaining myocardial energy production. Our findings highlight the primordial role of metabolic pathways and adipokines as therapeutic targets for HF management.
Source: medRxiv
Authors: Danielle Rasooly, Gina M. Peloso, Claudia Giambartolomei, Hannah L. Nicholls, Chang Liu, Nay Aung, Hesam Dashti, Kai Gravel-Pucillo, Jaime Berumen, Jesús Alegre-Díaz, Pablo Kuri-Morales, Roberto Tapia-Conyer, VA Million Veteran Program, John Whittaker, Peter W. F. Wilson, Lawrence S. Phillips, Kelly Cho, J. Michael Gaziano, Yan V. Sun, Jason M. Torres, Alexandre C. Pereira, Juan P. Casas, Jacob Joseph
Institutions: VA Boston Healthcare System, Boston University, Human Technopole, Queen Mary University of London, William Harvey Research Institute, Emory University, Broad Institute, Universidad Nacional Autónoma de México, Tecnológico de Monterrey, University of Cambridge, MRC Biostatistics Unit, Atlanta VA Health Care System, Atlanta VA Medical Center, Brigham and Women's Hospital, Harvard University, University of Oxford, Universidade de São Paulo, Instituto do Coração - HCFMUSP, Brown University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203606991