Atrial Fibrillation Polygenic Risk Score (AF-PRS) Predicts Non-Ischemic Cardiomyopathy: A Single-Center Retrospective Cohort Study of 16,801 Individuals

Abstract Background Non-ischemic cardiomyopathy (NICM) represents a major cause of heart failure with limited tools for early risk stratification. Atrial fibrillation (AF) is a well-established contributor to cardiomyopathy but is often clinically silent in its early stages. The atrial fibrillation polygenic risk score (AF-PRS) reflects genetic susceptibility to AF and may identify individuals at risk for AF-related cardiomyopathy. We hypothesized that higher AF-PRS is associated with greater risk of NICM. Methods This was a retrospective cohort study of 16,801 individuals of European ancestry from the Sanford Biobank and Imagenetics program with genetic sequencing and longitudinal electronic health record data. AF-PRS was calculated using 315 genome-wide significant single-nucleotide polymorphisms with standard quality control. NICM was defined by International Classification of Diseases, 10th Revision, Clinical Modification codes, excluding ischemic etiologies. Cox regression models evaluated the association between AF-PRS and incident NICM, adjusting for age, sex, smoking status, body mass index (BMI), hypertension, and diabetes. AF-PRS was analyzed both as a quasi-continuous variable (15% quartile increments) and dichotomized at the 85th percentile. Sensitivity analyses assessed associations with all-cause cardiomyopathy and ischemic cardiomyopathy. Survival analysis was used to model time-to-event outcomes. Results Among all participants, 418 (2.5%) had NICM. 99% were Caucasian. NICM cases were older and more often male (both p<0.001) than those without a diagnosis. After multivariable adjustment for sex, smoking status, BMI, and hypertension, a linear AF-PRS (15% increments) was specifically predictive of increased hazard risk of NICM (HR = 1.09 [1.03, 1.15], p < 0.001). Conclusion These findings complement recent evidence of bidirectional genetic relationships between cardiomyopathy and AF, supporting comprehensive genetic risk assessment in cardiovascular disease prevention. Clinical implementation requires validation in diverse populations and prospective evaluation. Future research should investigate the mechanistic pathways linking AF-associated genetic variants to cardiomyopathy development and evaluate whether AF-PRS-guided screening improves clinical outcomes. Visual abstract: Summary of study design, exposure, outcome, key findings, and clinical implications. This graphical abstract provides a comprehensive overview of the study investigating the association between atrial fibrillation polygenic risk score (AF-PRS) and non-ischemic cardiomyopathy (NICM). Abbreviations: AF, atrial fibrillation; AF-PRS, atrial fibrillation polygenic risk score; CI, confidence interval; HR, hazard ratio; ICD-10, International Classification of Diseases, 10th Revision; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; PPV, positive predictive value; PRS, polygenic risk score; SNP, single nucleotide polymorphism. Created in BioRender. https://BioRender.com/ k3t1w68