Shared Genetic Liability Between Heart Failure and Myocardial Infarction Revealed by Genome-Wide Cross-Trait...

Area of Science:

• Cardiovascular Genetics
• Genomics
• Complex Disease Etiology

Background:

• Shared genetic architecture between myocardial infarction (MI) and heart failure (HF) is not fully understood.
• Investigating the biological relevance of shared genetic factors is crucial for understanding disease mechanisms.

Purpose of the Study:

• To comprehensively analyze the shared genetic architecture between MI and HF.
• To identify pleiotropic loci and functional variants contributing to both conditions.

Main Methods:

• Genome-wide association studies (GWAS) summary statistics for MI and HF in European ancestry.
• Linkage disequilibrium score regression for genetic correlation and MiXeR for polygenic overlap.
• Conditional and conjunctional false discovery rate (condFDR/conjFDR) for locus identification.
• Functional prioritization using fine-mapping, TWAS, and proteomic data integration (SMR).

Main Results:

• Strong positive genetic correlation between MI and HF (rg = 0.494).
• Substantial polygenic overlap, with ~90% of MI variants shared with HF, and concordant effect directions.
• Identification of multiple pleiotropic loci and novel HF-associated regions; prioritized rs544366796 for MI.
• TWAS and FOCUS highlighted known MI genes and identified MYOZ1 as HF-specific; SMR suggested apolipoprotein E as a shared protein.

Conclusions:

• MI and HF share significant genetic liability through polygenic overlap and pleiotropic loci.
• Integrative analyses propose a potential two-stage genetic framework from ischemic susceptibility to HF progression.
• Findings provide a hypothesis-generating model for the genetic links between MI and HF.