Abstract
Brugada syndrome (BrS) has been associated with lower obesity rates and reduced body mass index (BMI) in observational studies. This Mendelian randomization (MR) study investigates causal effects of anthropometric traits on the risk of BrS. Two-sample MR analyses were conducted using publicly available genome-wide association study summary statistics, and both discovery and replication datasets were incorporated. The inverse-variance weighted method was the primary analytical approach, supported by MR-Egger and weighted median methods. Sensitivity analyses (including Cochran Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis) were performed to assess the robustness of the results. Genetically predicted comparative body size at age 10 showed significant inverse associations with BrS risk (discovery: odds ratio [OR] = 0.40, 95% confidence interval [CI]: 0.26-0.61, P = 2.07 × 10-5; replication: OR = 0.47, 95% CI: 0.31-0.71, P = 3.68 × 10-4). Similarly, adult obesity was inversely associated with BrS in the discovery set (OR = 0.78, 95% CI: 0.69-0.89, P = 1.42 × 10-4). Genetically predicted childhood obesity, whole-body fat-free mass, BMI, waist-to-hip ratio, and basal metabolic rate also demonstrated potential protective effects (discovery: all P < .05). Reverse MR analysis revealed positive associations between genetically predicted BrS and both waist and hip circumference (P < .005). This study suggests that genetically higher childhood/adult obesity and increased fat-free mass may reduce the risk of BrS. Maintaining a BMI in the upper-normal range and enhancing fat-free mass through resistance training may represent a viable strategy to mitigate BrS risk.