The Risk of Atrial Fibrillation Increases with Earlier Onset of Obesity: A Mendelian Randomization Study

Background: Obesity is a well-established risk factor for atrial fibrillation (AF). Previous epidemiological research on obesity and AF often focused on adult populations and now broadened to earlier in life. Therefore, this study aimed to determine the relationships between obesity at different periods of life and the risk of AF. Methods: A two-sample Mendelian randomization (MR) study design using summarised data from 6 genome-wide association studies (GWASs) was employed in this study. Single nucleotide polymorphisms (SNPs) associated with adult obesity, childhood obesity, childhood body mass index (BMI), waist-to-hip ratio adjusted for BMI (WHRadjBMI), birth weight and AF were independently retrieved from large-scale GWASs. For SNP identification, the genome-wide significance threshold was set at p <5.0010 -8 . To obtain causal estimates, MR analysis was conducted using the inverse variance-weighted (IVW) method. The weighted median, MR-Egger methods and MR-robust adjusted profile score (MR-RAPS) were used to evaluate the robustness of MR analysis. Results: A total of 204 SNPs were identified as the genetic instrumental variables (5 SNPs for childhood obesity, 13 SNPs for childhood BMI, 137 SNPs for birth weight, 35 SNPs for adult WHRadjBMI, and 14 SNPs for adult obesity). The results of MR analysis demonstrated that the genetically predicted adult obesity, childhood BMI, and birth weight were associated with AF risk. Notably, a 1 unit standard deviation (1-SD) increase in adult obesity was related to a 13% increased risk of AF [p=6.5110 - , OR, 1.13 (95% CI, 1.08-1.19)], a 1-SD increase in childhood BMI was related to a 18% increased risk of AF [p=1.7710 - , OR, 1.18 (95% CI, 1.08-1.29)], and a 1-SD increase in birth weight was related to a 26% increased risk of AF [p=1.2710 -7 , OR, 1.26 (95% CI, 1.16-1.37)]. There was no evidence of pleiotropy or heterogeneity between the MR estimates obtained from multiple SNPs. Conclusion: Our study reveals the association of genetic susceptibility to obesity with a higher risk of AF. Moreover, an earlier age at obesity was associated with an increased risk of AF. Therefore, public awareness of the dangers of obesity and active early weight control may prevent the development of AF.