Bidirectional two-sample Mendelian randomization study of association between smoking initiation and atrial fibrillation

Abstract

Introduction: The relationship between smoking and heart disease has been frequently reported. Therefore, we aimed to explore the association between smoking initiation and atrial fibrillation.

Methods: Genetic association data pertaining to smoking initiation and atrial fibrillation were obtained from genome-wide association studies (GWAS). Phenotypically related single nucleotide polymorphisms (SNPs) were selected as instrumental variables. Inverse-variance weighted (IVW), weighted median, Mendelian randomization (MR), Egger regression, simple mode, and weighted mode methods were employed to perform the MR study. The association between smoking initiation and atrial fibrillation was evaluated using odds ratios (OR) and 95% confidence intervals (CI). Cochran's Q test was employed to assess heterogeneity among instrumental variables, utilizing the IVW and MR-Egger methods. The Egger-intercept method was employed to test for horizontal pleiotropy, and the 'leave-one-out' method was utilized for sensitivity analysis.

Results: The MR results for the effect of smoking initiation on atrial fibrillation (IVW, OR=1.11; 95% CI: 1.02-1.20, p=0.013) supported an association between smoking initiation and an increased likelihood of atrial fibrillation. In total, 85 SNPs were extracted from the GWAS pooled data as instrumental variables. The MR-Egger method indicated an intercept close to 0 (Egger intercept= -0.005, p=0.371), suggesting no horizontal pleiotropy in the selected instrumental variables. The 'leave-one-out' sensitivity analysis demonstrated that the results were robust and that no instrumental variables significantly influenced the results. Reverse MR analysis indicated no effect of atrial fibrillation on smoking initiation (IVW, OR=1.00; 95% CI: 0.99-1.02, p=0.684).

Conclusions: Smoking initiation has a significant impact on atrial fibrillation. However, atrial fibrillation did not influence smoking initiation. This study provides novel insights into the genetic relationships between smoking initiation and atrial fibrillation.

Keywords: atrial fibrillation; smoking initiation; two-sample Mendelian randomization.

Figure 1

Scatter plot of the effect of smoking initiation on atrial fibrillation, IEU OpenGWAS 2018–2019 (N=372249)

Figure 2

Forest plot of the effect of smoking initiation on atrial fibrillation, IEU OpenGWAS 2018–2019 (N=372249)

Figure 3

Funnel plot of the effect of smoking initiation on atrial fibrillation, IEU OpenGWAS 2018–2019 (N=372249)

Figure 4

Sensitivity analysis of the effect of smoking initiation on atrial fibrillation, IEU OpenGWAS 2018–2019 (N=372249)