Shared Genetic Liability Between Heart Failure and Myocardial Infarction Revealed by Genome-Wide Cross-Trait Analysis
Journal of Cardiovascular Pharmacology and Therapeutics, 2026
Liu R., Sun C., Jiang N., Liu Y., Li J., Zhang F., Chen C., Liu Y., Qi X., Guo B., Yang K.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
The extent and biological relevance of shared genetic architecture between myocardial infarction (MI) and heart failure (HF) remain incompletely understood.
Methods
We analyzed large-scale European-ancestry genome-wide association studies summary statistics for MI and HF. Genome-wide genetic correlation was estimated using linkage disequilibrium score regression, and polygenic overlap was quantified using MiXeR. Shared loci were identified via conditional and conjunctional false discovery rate (condFDR/conjFDR) approaches. Functional prioritization incorporated Functional Mapping and Annotation-based annotation, Bayesian fine-mapping, transcriptome-wide association studies (TWAS), FOCUS gene fine-mapping, and summary-level Mendelian randomization (SMR) integrating UKB-PPP proteomic data.
Results
Linkage disequilibrium score regression revealed a robust positive genetic correlation between MI and HF (rg = 0.494, P = 1.12 × 10 −15 ). MiXeR demonstrated substantial polygenic overlap, with approximately 90% of MI-associated variants shared with HF and strong concordance in effect direction. The cond/conjFDR analyses identified multiple pleiotropic loci, including novel HF-associated regions. Fine-mapping prioritized rs544366796 within the SLC22A2/SLC22A3 locus as a high-confidence candidate variant for MI based on posterior probability. The TWAS and FOCUS highlighted canonical MI genes (CDKN2B, CELSR2, BRAP, NBEAL1) and identified MYOZ1 as an HF-specific candidate gene. Proteome-wide SMR analysis provided statistical evidence consistent with apolipoprotein E being a shared protein influenced by variants associated with both MI and HF.
Conclusion
The MI and HF share substantial genetic liability characterized by strong polygenic overlap and pleiotropic loci. Our integrative analyses suggest a potential 2-stage genetic framework linking ischemic susceptibility to myocardial remodeling and HF progression, which should be interpreted as a hypothesis-generating conceptual model rather than direct evidence of temporal progression.