Abstract Body (Do not enter title and authors here): Background: Heart failure (HF) is a leading global cause of morbidity and mortality. Despite therapeutic advances, effective strategies for the primary prevention for HF are limited— particularly in subpopulations where clinical trials have yielded inconclusive benefits. Integrating human proteomic and transcriptomic data can detect key molecular pathways driving HF. Further, multi-ancestry genetic analyses enhance the power to identify causal genomic signals. These complementary approaches provide a framework for identifying and prioritizing novel therapeutic targets for HF.

Methods: We conducted large-scale, systematic Mendelian randomization analyses using genome-wide association study (GWAS) data on all-cause HF, comprising 221,295 cases and 2,638,963 control individuals of European, African, Hispanic, and Asian populations from the Million Veteran Program (MVP) and other large biobanks and consortia. Using gene expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to instrument 15,527 genes, we applied cis-Mendelian randomization (MR) to generate putative causal evidence for druggable genes implicated in HF. We prioritized druggable genes and triangulated findings with orthogonal biological evidence to support validation programs in preclinical models.

Results: We identified 105 genome-wide significant loci associated with all-cause HF, and 54 putatively causal genes, including 21 novel targets. We observed ancestry- and subtype-specific differences in the strength and direction of genetic effect estimates for the identified genes, suggesting biologically distinct pathways that may inform the prioritization of novel drug targets. To strengthen causal inference and therapeutic relevance, we provide a therapeutic target profile for each identified gene, incorporating predicted efficacy, on-target safety, novelty of biological mechanism, druggability, and mechanism of action. Several biological pathways emerged as potential therapeutic targets for HF, including those related to inflammation and cholesterol ester hydrolysis.

Conclusions: This study represents, to our knowledge, the largest genetics study on HF conducted to date. Our findings underscore the value of human genetic and metabolic evidence in identifying novel therapeutic targets for HF. Supporting evidence from orthogonal sources validates their efficacy and offers insight into potential mechanisms of action, informing the development of targeted HF therapies.