A Genomic Convergence: Mapping Shared Causal Loci between Heart Failure and Arrhythmias

Heart failure (HF) and various arrhythmias frequently co-occur in clinical practice, suggesting shared pathophysiological mechanisms. However, the extent and nature of their common genetic architecture remain incompletely understood. This study aimed to systematically investigate the genetic correlations and shared causal loci between HF-related traits and multiple arrhythmia phenotypes.

We utilized genome-wide association study summary statistics from European cohorts to analyze HF-related traits and ten common arrhythmias. Global genetic correlations were assessed using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Local genetic correlations were further investigated using local analysis of [co]variant annotation, Heritability Estimation from Summary Statistics, and super generalized variance decomposition to identify regional overlaps. Pleiotropic loci were identified using pleiotropic analysis under composite null hypothesis, with Bayesian co-localization analysis (stringent threshold posterior probability of hypothesis 4 [PP.H4] ≥ 0.75) to assess shared causality. Bidirectional Mendelian randomization (MR) was conducted to explore causal relationships, utilizing a discovery threshold (p < 5 × 10-6) and a validation threshold (p < 5 × 10-8) with independent FinnGen data.

Significant genome-wide genetic correlations were identified between HF and seven arrhythmia traits, with the strongest association for atrial fibrillation (AF) (LDSC: rg = 0.42, p = 5.1 × 10-18; HDL: rg = 0.63, p = 5.9 × 10-37). Local genetic correlation analyses identified multiple genomic regions of significant overlap, particularly converging on a major hotspot at the 4q25/PITX2/ENPEP locus across all three methods. Pleiotropic analysis identified several high-confidence shared loci, including regions harboring BAG3 (PP.H4 = 0.990) and ZFHX3 (PP.H4 = 0.938). Bidirectional MR revealed significant causal effects of AF on HF development (inverse variance-weighted odds ratio = 1.22, p = 4.83 × 10-18) and HF on reduced heart rate variability (p = 1.86 × 10-4), both validated in independent cohorts.

Our findings demonstrate substantial and complex shared genetic architecture between HF and multiple arrhythmia phenotypes. These insights identify specific pleiotropic genes, regional correlation hotspots, and causal pathways, potentially informing future precision medicine approaches for cardiovascular disease prevention and treatment.