Heart failure (HF) is a common and serious condition, yet identifying individuals at greatest risk—especially before symptoms appear—remains a challenge. In this study, we introduce and validate a new genetic testing approach designed to predict HF susceptibility, leveraging data from three separate Australian and US cohorts. The first phase utilized the Baker Biobank case–control cohort, revealing 41 genetic variants associated with HF risk through genome-wide association and interaction analyses. A second phase expanded the panel with 29 additional single-nucleotide polymorphisms, and combining both phases produced a comprehensive test demonstrating strong predictive performance, with an Area Under the Curve (AUC) of 0.93 and balanced accuracy of 0.89. Participants identified as high genetic risk in the Baker Biobank cohort showed an odds ratio of 533.2. External validation in the Busselton Health Study and Atherosclerosis Risk in Communities cohorts confirmed the test’s reliability, with AUCs of 0.83 and 0.72, balanced accuracies of 0.76 and 0.67, and odds ratios of 12.3 and 4.6, respectively. These results highlight the significant contribution of genetic factors to HF and indicate that this test could provide a powerful tool for early, personalized HF risk prediction.
