Abstract Body (Do not enter title and authors here): Background: Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unravelled. We examined the impact of putative disease-causing ventricular cardiomyopathy variants (PDCv) on AF and ventricular cardiomyopathy risk in the UK Biobank (UKB).
Methods: Cox regression was used to evaluate for associations between PDCv within ClinGen “Definitive”/”Strong”/”Moderate” evidence genes for 3 cardiomyopathies (dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], and arrhythmogenic right ventricular cardiomyopathy [ARVC]) and AF. Disease-specific polygenic risk scores (PRSs) for AF, DCM, and HCM were used to stratify study participants into quintiles. The Kaplan-Meier method was used to assess the cumulative incidence from birth to age 75 for AF, DCM, and HCM stratified by carrier status of a PDCv and disease-specific PRS quintile.
Results: Among 346,260 UKB study participants, presence of a PDCv was associated with an increased AF hazard (HR 1.77, 95% CI 1.65 – 1.90; p<0.001), including when restricted to study participants without ventricular cardiomyopathy or heart failure (HR 1.57, 95% CI 1.43 – 1.72, p<0.001). Subdivided by cardiomyopathy gene subtype, carriers of PDCv within DCM (HR: 2.16, 95% CI: 1.98-2.36; p<0.001), ARVC (HR: 1.35, 95% CI: 1.09-1.66; p=0.005) and HCM (HR: 1.31, 95% 1.14 – 1.51; p<0.001) genes all had statistically significant increased hazards of AF. Relative to study participants in the lowest PRS_AF quintile without a rare PDCv, study participants in the top PRS_AF quintile with a PDCv had a 7.26-fold increased hazard of AF (95% CI 6.29–8.38, p<0.001). The cumulative AF risk for study participants with a rare PDCv and a PRS_AF in the top risk quintile was 39.6% relative to 6.7% for study participants without a PDCv and a PRS_AF in the lowest risk quintile. The absolute cumulative cardiomyopathy risk among study participants with both a rare PDCv and a disease-specific PRS within the top risk quintile was 5.1% for DCM and 12.3% for HCM.
Conclusions: Putative disease-causing variants within ventricular cardiomyopathy genes are associated with an increased risk of AF in the absence of ventricular cardiomyopathy and clinical heart failure. Despite these genes having been originally identified as culprits for ventricular cardiomyopathy, when integrated with a disease-specific PRS, their impact on the absolute risk for incident AF appears larger relative to that observed for incident DCM and HCM.