Abstract MP13: Polygenic Susceptibility to Atrial Fibrillation is Associated With Silent Cerebrovascular Disease in Stroke-Free Persons Without Atrial Fibrillation

Abstract

Introduction: Clinically silent cerebrovascular disease is present in 40% of persons over the age of 60. We hypothesize that polygenic susceptibility to atrial fibrillation is associated with the burden of white matter disease in persons without atrial fibrillation or history of ischemic stroke. Methods: We conducted a nested genetic and neuroimaging study within the UK Biobank, a large cohort study that enrolled community dwelling Britons aged 40 to 65 at recruitment. We used data on a subcohort of patients evaluated with brain MRIs. The volume of white matter hyperintensities (WMH) was estimated using the BIANCA lesion segmentation tool. Genomic data was ascertained via genotyping with the Affymetrix UK Biobank Axiom array followed by imputation with 1000 Genomes reference panels. To model the polygenic susceptibility to atrial fibrillation (AFIB), we constructed a polygenic risk score (PRS) using 957 independent genetic risk variants known to significantly associate with atrial fibrillation. We used logistic and linear regression to test for association between the PRS and WMH. Results: A total of 38,914 study participants underwent brain MRI imaging in the UK Biobank. Of these, we excluded 124 (0.3%) with a history of stroke and 926 (2.4%) with AFIB. 37,864 study participants were included in this study, of which 19,059 (50.3%) had WMH. High genetic risk of AFIB was not associated with no-versus-any WMH (p=0.51). When evaluating persons with WMH lesions, high genetic risk of AFIB was associated with higher WMH volume (per 1 SD increase of the PRS, beta 0.019, SE 0.006; p=0.01). Gender was an important effect modifier of this association (interaction p=0.03): while high genetic risk of AFIB was associated with a significant increase in WMH volume in females (per 1 SD increase of the PRS, beta 0.03, SE 0.008; p<0.001), no association was found for males (p=0.99). Conclusions: Polygenic susceptibility to atrial fibrillation is associated with more severe silent cerebrovascular disease in persons without atrial fibrillation. Further research should evaluate whether this genetic information can be used to identify persons for tailored diagnostic or therapeutic interventions.