Are Atrial Fibrillation Risk Loci Universally Applicable? Insights from Whole-Genome Sequencing in a Polish Population

<b>Background:</b> Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and has a substantial genetic component. Genome-wide association studies (GWASs) have identified more than 100 susceptibility loci; however, replication across populations remains variable, suggesting potential population-specific differences in the genetic determinants of AF. To date, no whole-genome sequencing (WGS)-based study has evaluated AF susceptibility in a Polish population. <b>Methods:</b> We performed WGS (mean coverage 35×) in 233 unrelated individuals recruited within the Thousand Polish Genomes Project, including 56 patients with non-valvular AF and 177 controls without AF. After quality control and linkage disequilibrium pruning within a cardiovascular gene panel, 19,395 variants were analyzed. Association testing was performed using logistic regression adjusted for age and sex, applying both false discovery rate and Bonferroni correction thresholds. <b>Results:</b> No variants reached statistical significance for association with AF after correction for multiple evaluation. Previously reported susceptibility loci were not replicated in this cohort. Age was strongly associated with AF risk, whereas sex showed no significant effect. Given the relatively modest sample size, the study was primarily powered to detect variants with moderate or large effect sizes; smaller genetic effects reported in large GWASs may remain undetected. <b>Conclusions:</b> This pilot WGS-based study provides an initial exploration of AF-associated genetic variation in a Polish population. The absence of significant associations likely reflects the importance of further investigation in larger and well-characterized Central-Eastern European cohorts before genetic risk stratification approaches can be broadly applied across populations.