A Novel Transcriptome-Wide Association Study Identifies USP36 as a Potential Therapeutic Target for Heart Failure

Heart failure is a significant global health burden. This study aims to identify heart failure–associated genes through transcriptome-wide association studies combined with genome-wide association studies. A transcriptome-wide association study was conducted using Functional Summary-based Imputation, integrating heart failure genome-wide association study summary data (47,309 cases and 930,014 controls) with Genotype-Tissues Expression Project V8 expression quantitative trait loci data from 49 tissues. Gene-level analysis was performed using Multi-marker Analysis of Genomic Annotation, followed by mendelian randomization and Bayesian colocalization. The functional implications of candidate genes were explored using GeneMANIA, and the druggability of the top gene, USP36, was evaluated via molecular docking simulations. Functional Summary-based Imputation and Multi-marker Analysis of Genomic Annotation analyses identified 26 candidate genes. Further investigation highlighted USP36 as significant, particularly in left ventricular tissue, where it confers protection against heart failure. GeneMANIA showed that USP36 interacts with genes involved in oxidative stress-induced apoptosis, suggesting its role in heart failure pathogenesis. Molecular docking simulations confirmed USP36’s binding affinity with heart failure therapeutics, supporting its potential as a therapeutic target. USP36 is a novel heart failure susceptibility gene and a promising therapeutic target. Its involvement in oxidative stress-related pathways offers new insights into heart failure risk and warrants further investigation for disease development and treatment.