Abstract
AIMS: Observational studies report conflicting results on the relationship between QRS duration and chronic heart failure (CHF), presenting challenges in establishing a causal link. This study investigates the heritability of QRS duration and CHF and their causal relationship. METHODS AND RESULTS: Genome-wide association studies (GWAS) cohort for QRS duration included 10 815 samples from the IEU Open GWAS project, while exome-wide association studies (EWAS) data were sourced from the CHARGE Exome-Chip EKG consortium, involving 77 898 European individuals. The CHF GWAS dataset comprised 486 160 samples from the EMBL-EBI GWAS catalogue. Heritability estimates were determined using linkage disequilibrium score regression (LDSC). Mendelian randomization (MR) and sensitivity analyses assessed the causality. Heritability estimates for QRS duration were 16.3% from GWAS and 18.5% from EWAS. CHF exhibited minimal genetic influence with a heritability estimate of 0.8%. Six variants from the GWAS and 27 variants from the EWAS, including those in ion channel-related genes, like CASQ2, SCN5A and SCN10A, were identified as instrumental variables. MR analysis indicated that shorter QRS duration is causally associated with an increased CHF risk [QRS GWAS: (IVW (MRE): OR 0.84, 95% CI 0.78-0.91, P = 2.26E-05); QRS EWAS: (IVW (MRE): OR 0.98, 95% CI 0.96-0.99, P = 6.57E-05)]. Sensitivity analyses confirmed the robustness of these findings [corrected GWAS: Egger_intercept = 0.002, P = 0.94; corrected EWAS: Egger_intercept = 0.007, P = 0.38]. CONCLUSIONS: This study establishes a causal relationship between shorter QRS duration and increased CHF risk, highlighting the importance of genetic factors in cardiac electrical conduction. Identifying QRS duration as a genetic marker for CHF risk can enhance early diagnosis and personalized treatment strategies.