Multi-trait genome-wide analysis identified risk loci and candidate drugs for heart failure

Heart failure (HF) is a common cardiovascular syndrome that poses significant morbidity and mortality risks. While genome-wide association studies reporting on HF abound, its genetic etiology remains poorly elucidated, primarily due to its inherent polygenic nature. Furthermore, these genetic insights have not been fully leveraged to develop effective primary treatment strategies for HF. In this study, we conducted a large-scale integrated multi-trait analysis using European ancestry genome-wide association study summary statistics of coronary artery disease and HF, involving nearly 2 million samples to identify risk loci associated with HF. Seventy-two loci were identified for HF using MTAG, of which 58 were supported in the replication phase. Transcriptome association analysis revealed 215 HF risk genes, including EDNRA and FURIN. Pathway enrichment analysis of risk genes revealed their enrichment in pathways closely related to HF, such as response to endogenous stimulus (adjusted p = 8.83 × 10^-3), phosphate-containing compound metabolic process (adjusted p = 1.91 × 10^-2), myofibroblast differentiation (adjusted p = 4.26 × 10^-2), and regulation of muscle adaptation (adjusted p = 4.96 × 10^-2). Single-cell analysis indicated significant enrichments of these genes in smooth muscle cells, fibroblasts of cardiac tissue, and cardiac endothelial cells. Additionally, our analysis of HF risk genes identified 81 potential drugs for further pharmacological evaluation. These findings provide insights into the genetic determinants of HF, highlighting MTAG-identified genetic loci as potential interventional targets for HF treatment, with significant implications for public health and clinical practice.