Abstract Body (Do not enter title and authors here): Background: Prior population-based cohort studies demonstrate that an atrial fibrillation (AF)-specific polygenic risk score (AF-PRS) is an independent predictor of incident AF. Further data on the performance of the AF-PRS in a real-world population may inform AF screening techniques in high-risk patients.

Objective: The objective of the current study is to evaluate the association between an AF-PRS and incidence of AF in a real-world cohort.

Methods: Data from the Endeavor Health Genomic Health Initiative (GHI), utilizing DNA from blood samples of consenting patients, were analyzed. All participants in the GHI with complete genetic information (low pass whole genome sequencing with imputation) and without an existing diagnosis of AF (per ICD-10 codes) were included and followed through a censoring date of 7/21/2023. AF-PRS (PGS002756) was calculated for each patient. A high-risk AF-PRS was defined as 1.5x relative risk for AF based on the UK biobank, which corresponds to the 13^th percentile of risk. Multivariate analyses were completed to determine associations between this AF-PRS and outcome variables.

Results: There were 15,803 patients in the GHI (53.7yrs [52.4-53.9], 34.3% male) followed for a median of 8 years. Among them, 2,206 (14.0%) had a high-risk AF-PRS. Those with high-risk AF-PRS were less likely to be male, had a higher BMI, and a greater percentage of family history of AF (Table). A high AF-PRS risk, compared to low AF-PRS risk, was associated with greater incidence of AF (HR 1.89 [1.55-2.31], p<0.001) after adjusting for age at recruitment, gender, and genetic background (top 10 ancestry principal components) (Fig 1). Those with a high-risk AF-PRS also had a younger age at AF diagnosis (Fig 2).

Conclusions: In a real-world cohort of patients with complete genetic sequencing, a high-risk, compared to low-risk, AF-PRS was associated with greater incidence of AF and younger age at AF diagnosis. The findings, along with other risk factors, could provide a rationale for screening measures in selected patients at increased risk of developing AF.