Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Area of Science:

• Genetics
• Cardiovascular Medicine
• Genomics

Background:

• Heart failure (HF) is a major global health burden with largely unexplained heritability.
• Existing genome-wide association studies (GWAS) have provided limited insights into HF's genetic architecture.
• Monogenic cardiomyopathies account for only a small fraction of HF cases.

Purpose of the Study:

• To identify novel genetic loci associated with heart failure.
• To explore the shared genetic etiology between heart failure and related cardiovascular diseases.
• To investigate the functional roles of newly identified genes in HF pathogenesis.

Main Methods:

• Conducted a large-scale GWAS meta-analysis of HF, including 47,309 cases and 930,014 controls.
• Performed functional analysis of identified genetic loci.
• Utilized Mendelian randomization to assess causal relationships between risk factors and HF.

Main Results:

• Identified 12 independent variants at 11 genomic loci associated with HF.
• Observed shared genetic associations between HF, coronary artery disease (CAD), atrial fibrillation, and left ventricular function.
• Functional analyses implicated genes in cardiac development, protein homeostasis, and cellular senescence.
• Mendelian randomization supported causal roles for several HF risk factors and identified CAD-independent effects for atrial fibrillation, BMI, and hypertension.

Conclusions:

• The study expands the understanding of genetic pathways underlying HF.
• Identified genetic variants suggest shared etiology with other cardiovascular conditions.
• Findings may guide the development of novel therapeutic strategies for heart failure.