Genetic Risk Prediction of Atrial Fibrillation

Abstract

Background Atrial fibrillation (AF) is common and has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 controls. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1×10−3 to <1×10−8 in a prior independent genetic association study. Results Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13–1.46; P=1.5×10−4) to 1.67 (25 variants; 95%CI, 1.47–1.90; P=9.3×10−15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke, versus those in the lowest quartile (95%CI, 1.39–4.58; P=2.7×10−3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20–4.40; P=0.01). Conclusions Comprehensive AF genetic risk scores were associated with incident AF beyond clinical AF risk factors, with magnitudes of risk comparable to other clinical risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts to determine whether AF genetic risk may improve identification of subclinical AF or distinguish stroke mechanisms are warranted.

Heritability of Atrial Fibrillation

“…37 In contrast, our comprehensive AF definition included self-report, ICD9 and ICD10 codes, and AF-related procedures such as catheter ablation, which likely minimized misclassification of AF cases as referents. Genetic risk for AF has previously been associated with a variety of clinical outcomes including incident AF, 38, 39 ischemic stroke, 39, 40 and variably with catheter ablation success, 41 though any potential clinical application of genetic risk information may be highly context-dependent. Whether the magnitude of AF risk explained by genome-wide variation, or perhaps family history of AF, will contribute meaningfully to clinical risk assessment warrants further evaluation.…”

Genomic basis of atrial fibrillation

“…Moreover, in a separate sample, we observed that AF genetic risk was associated with cardioembolic stroke even in the absence of clinically recognised AF (figure 3). 32 …”

Year in Review in Cardiac Electrophysiology

“…By combining 5 study cohorts of 18 191 individuals, Lubitz et al 9 analyzed predictors of incident AF, as well as subsequent complications, such as stroke. They found that while a genetic risk score was associated with incident AF (maximum C statistic, 0.629-0.811), it added only marginally to clinical risk prediction (maximum ΔC statistic from clinical score alone, 0.009-0.017).…”