Heart failure (HF) is a common cardiovascular disease that poses significant morbidity and mortality risks. While genome-wide association studies reporting on HF abound, its genetic etiology is not well understood due to its inherent polygenic nature. Moreover, these genetic insights have not been completely translated into effective strategies for the primary treatment of HF. In this study, we conducted a large-scale integrated multi-trait analysis using European-ancestry GWAS summary statistics of coronary artery disease and HF, involving near 2 million samples to identify novel risk loci associated with HF. 72 loci were newly identified with HF, of which 44 were validated 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 = 8.83e-3), phosphate-containing compound metabolic process (adjusted P = 1.91e-2). Single-cell analysis indicated significant enrichments of these genes in smooth muscle cells, fibroblast of cardiac tissue, and cardiac endothelial cells. Additionally, our analysis of HF risk genes identified 74 potential drugs for further pharmacological evaluation. These findings provide novel insights into the genetic determinants of HF, highlighting new genetic loci as potential interventional targets to HF treatment, with significant implications for public health and clinical practice.

The authors have declared no competing interest.

This work was supported by the Guangdong Basic and Applied Basic Research Foundation under Grant 2022A1515-011426, in part by the National Natural Science Foundation of China under Grant 61873027, Grant 81970200 and Grant 82271609, in part by the Guangzhou Municipal Science and Technology Project under Grant 2023B01J1011, and in part by the Shenzhen Science and Technology Program under Grant JCYJ20190808100817047 and Grant RCBS20200714114909234.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The datasets analyzed during the current study are publicly available. GWAS summary statistics data for discovery phase are available from GWAS Catalog under study accessions GCST009541 and GCST90132314 at https://www.ebi.ac.uk/gwas/. GWAS summary statistics data for replication phase are available at https://storage.googleapis.com/finngen-public-data-r7/summary_stats/finngen_R7_I9_HEARTFAIL_ALLCAUSE.gz and https://storage.googleapis.com/finngen-public-data-r7/summary_stats/finngen_R7_I9_CHD.gz. Data used in LDSC analysis can be obtained at https://alkesgroup.broadinstitute. org/LDSCORE/. JTI models of gene expression in 8 heart tissues are available from Zenodo at http://doi.org/10.5281/zenodo.3842289. Single-cell data used in scDRS analysis are available from Tabula Sapiens Single-Cell Dataset at https://doi.org/10.6084/m9.figshare.14267219.v5. All drug information is available from Drugbank v.5 at https://go.drugbank.com/. The information on all mouse knockout models can be obtained from Mouse Genome Informatics resources at https://www.informatics.jax.org/

https://www.ebi.ac.uk/gwas/

https://alkesgroup.broadinstitute.org/LDSCORE/

http://doi.org/10.5281/zenodo.3842289

https://doi.org/10.6084/m9.figshare.14267219.v5

https://go.drugbank.com/