Abstract
BackgroundAtrial fibrillation (AF) and brain volume loss are prevalent in older individuals. We aimed to assess the causal effect of atrial fibrillation on brain volume phenotypes by Mendelian randomization (MR) analysis.MethodsThe genetic instrument for AF was constructed from a previous genome-wide association study (GWAS) meta-analysis (15,993 AF patients and 113,719 controls of European ancestry). The outcome summary statistics for head-size-normalized white or gray matter volume measured by magnetic resonance imaging were provided by a previous GWAS of 33,224 white British participants in the UK Biobank. Two-sample MR by the inverse variance–weighted method was performed, supported by pleiotropy-robust MR sensitivity analysis. The causal estimates for the effect of AF on ischemic stroke were also investigated in a dataset that included the findings from the MEGASTROKE study (34,217 stroke patients and 406,111 controls of European ancestry). The direct effects of AF on brain volume phenotypes adjusted for the mediating effect of ischemic stroke were studied by multivariable MR.ResultsA higher genetic predisposition for AF was significantly associated with lower grey matter volume [beta −0.040, standard error (SE) 0.017, P=0.017], supported by pleiotropy-robust MR sensitivity analysis. Significant causal estimates were identified for the effect of AF on ischemic stroke (beta 0.188, SE 0.026, P=1.03E−12). The total effect of AF on lower brain grey matter volume was attenuated by adjusting for the effect of ischemic stroke (direct effects, beta −0.022, SE 0.033, P=0.528), suggesting that ischemic stroke is a mediator of the identified causal pathway. The causal estimates were nonsignificant for effects on brain white matter volume as an outcome.ConclusionsThis study identified that genetic predisposition for AF is significantly associated with lower gray matter volume but not white matter volume. The results indicated that the identified total effect of AF on gray matter volume may be mediated by ischemic stroke.
Highlights
Atrial fibrillation (AF) and brain volume loss are prevalent in older individuals
Causal estimates of AF on brain volume The summary-level Mendelian randomization (MR) results indicated that genetic predisposition for AF was significantly associated with lower gray matter volume, both normalized and unnormalized (Figs. 2 and 3 and Table 1)
The MR-Egger intercept P value indicated the absence of a directional pleiotropic effect, and the effect size of the causal estimates by MR-Egger regression was generally similar to the other methods
Summary
Atrial fibrillation (AF) and brain volume loss are prevalent in older individuals. We aimed to assess the causal effect of atrial fibrillation on brain volume phenotypes by Mendelian randomization (MR) analysis. Whether AF alone can cause brain volume loss even without stroke needs to be studied, as previous reports assessed the association between AF and dementia in stroke-free individuals, and brain volume loss was present before the identified first stroke event in AF patients [5, 9, 10]. Such evidence for the causal effect of AF on brain volume and its mechanistic association with stroke would suggest whether accelerated brain volume loss in AF patients may be ameliorated through appropriate AF management targeting the risk of ischemic stroke
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