Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.

Summary

A GWAS meta-analysis of 1.9 million individuals identified 66 loci for heart failure (37 novel), prioritized effector genes, and mapped them to etiologic clusters using phenome-wide association, network analysis, and colocalization. Heritability enrichment implicated extracardiac tissues, and Mendelian randomization revealed differential upstream risk factor associations across HF subtypes.

Key Findings

• Identified 66 genetic loci associated with HF and subtypes, including 37 previously unreported.
• Functionally prioritized effector genes and mapped loci to etiologic disease clusters via PheWAS, networks, and colocalization.
• Heritability enrichment analyses highlighted roles for extracardiac tissues in HF etiology.
• Mendelian randomization demonstrated differential associations of upstream risk factors across HF subtypes.

Clinical Implications

Genetic loci and prioritized genes can inform risk prediction and drug target discovery, while subtype-specific causal factor differences support tailored prevention strategies.

Limitations

• Subtype analyses were based on smaller subsets (e.g., ni-HF with preserved vs reduced EF), potentially reducing power
• Potential ancestry imbalance and heterogeneity across cohorts may affect transferability

Future Directions

Functional validation of prioritized genes and pathways; development of subtype-specific polygenic scores and druggable targets; inclusion of diverse ancestries.