Population-Level Prevalence of Rare Variants Associated With Atrial Fibrillation and its Impact on Patient Outcomes

Whole exome sequencing may identify rare pathogenic/likely pathogenic variants (LPVs) that are linked to atrial fibrillation (AF). The impact of LPVs associated with AF on a population level on outcomes is unclear. This study sought to examine the association of LPVs with AF and their impact on clinical outcomes using the UK Biobank, a national repository of participants with available whole exome sequencing data. A total of 200,631 individuals in the UK Biobank were studied. Incident and prevalent AF, comorbidities, and outcomes were identified using self-reported assessments and hospital stay operative, and death registry records. LPVs were determined using arrhythmia and cardiomyopathy gene panels with LOFTEE and ClinVar to predict variants of functional significance. Compared with control subjects, there was a modestly increased prevalence of LPVs among 9,585 patients with AF (2.0% vs 1.7%, respectively; P = 0.01). Among those with prevalent AF at <45 years of age, 4.2% were LPV carriers. LPVs in TTN and PKP2 were associated with AF with adjusted odds ratios of 2.69 (95% CI: 1.57-4.61) and 2.69 (95% CI: 1.54-4.68), respectively. There was no significant difference in combined ischemic stroke, heart failure hospitalization, and mortality among patients who have AF with and without LPVs (25.1% vs 23.8%; P = 0.49). Among participants with AF and available cardiac magnetic resonance imaging data, LPV carriers had lower left ventricular ejection fractions than non-LPV carriers (42% vs 52%; P = 0.027). Patients with AF had a modestly increased prevalence of LPVs. Among reference arrhythmia and cardiomyopathy genes, the contribution of rare variants to AF risk at a population level is modest and its impact on outcomes appears to be limited, despite an association of LPVs with reduced left ventricular ejection fraction among patients with AF.