Multi-ancestry genetic architecture of heart failure subtypes
Abstract Heart failure (HF) affects 6.7 million people in the US and includes two major subtypes, HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), with distinct genetic architectures. We meta-analyze genome-wide association studies (GWAS) of 38,781 HFrEF cases, 38,163 HFpEF cases, and 526,135 controls across European, African, Hispanic, and Asian ancestries using the Million Veteran Program and Vanderbilt University DNA Databank (BioVU). We identify 46 genome-wide significant loci for HFrEF (9 novel) and 3 loci for HFpEF (1 novel). Four HFrEF loci are detected in African ancestry participants near CD36, SPI1, TRIM48 , and SPNS3 , with lead SNPs showing low risk-allele frequencies in European populations. In the all-cause HF meta-analysis (200,070 cases, 2,076,466 controls), we identify 136 loci (12 novel). Gene-based tests, tissue enrichment, transcriptome-wide association, and fine-mapping implicate vascular, metabolic, and TGF-β/Smad signaling pathways and nominate candidate causal genes, clarifying shared and subtype-specific risk across ancestries.
Authors
- Peter W.F. Wilson (ORCID: https://orcid.org/0000-0002-5653-7056)
- Danielle Rasooly (ORCID: https://orcid.org/0000-0001-7715-1809)
- David C. Benkeser (ORCID: https://orcid.org/0000-0002-1019-8343)
- Nobuyuki Enzan (ORCID: https://orcid.org/0000-0002-3899-4405)
- Eric Farber‐Eger (ORCID: https://orcid.org/0000-0003-0281-3796)
- Gregorio V. Linchangco (ORCID: https://orcid.org/0009-0001-2578-9947)
- Yi‐Juan Hu (ORCID: https://orcid.org/0000-0003-2171-9041)
- Yan V. Sun (ORCID: https://orcid.org/0000-0002-2838-1824)
- Jacob Joseph (ORCID: https://orcid.org/0000-0002-7279-4896)
- Viola Vaccarino (ORCID: https://orcid.org/0000-0002-9054-0654)
- Lawrence S. Phillips (ORCID: https://orcid.org/0000-0002-6542-8046)
- Qin Hui (ORCID: https://orcid.org/0000-0002-8421-3518)
- Arshed Ali Quyyumi (ORCID: https://orcid.org/0000-0002-8166-679X)
- Chang Liu (ORCID: https://orcid.org/0000-0002-8918-7224)
- Kaoru Ito (ORCID: https://orcid.org/0000-0003-1843-773X)
- Quinn S. Wells (ORCID: https://orcid.org/0009-0009-4141-1520)
- VA Million Veteran Program
- J. Michael Gaziano
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Emory University (US)
- Chiba University (JP)
- Vanderbilt University (US)
- Brown University (US)
- VA Boston Healthcare System (US)
- Providence VA Medical Center (US)
- Massachusetts General Hospital (US)
- Atlanta VA Health Care System (US)
- RIKEN Center for Integrative Medical Sciences (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-13
- DOI
- https://doi.org/10.1038/s41467-026-76438-y
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Office of Research and Development
- National Institutes of Health
- Office of Academic Affiliations, Department of Veterans Affairs
- National Heart, Lung, and Blood Institute