Causality of Childhood and Adult Body Mass Index on Sick Sinus Syndrome: A Mendelian Randomization Study

Background The relationship between body mass index (BMI) and the risk of sick sinus syndrome (SSS) remains unclear. Clarifying the impact of BMI on SSS at different life stages is essential for advancing precision medicine and implementing effective prevention strategies to reduce the burden of SSS. Methods The causalities of childhood and adult BMI with SSS were investigated by univariate and multivariate Mendelian randomization. Reverse causalities were also explored to improve the accuracy of causality findings. Different sources of exposure data were used for replication analysis, and the effects of sample overlap were investigated using MRlap. The stability of the results was further enhanced through meta-analysis. Results There was a positive correlation of adult BMI with the risk of SSS in both the FinnGen (odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.01-1.35, P = 0.031) and Integrative Epidemiology Unit (IEU) open genome-wide association study (GWAS) project (OR = 1.18, 95% CI 1.04-1.34, P = 0.009) databases. The causality remained valid after the correction of telomere length. There was no causality detected between childhood BMI and SSS, as determined by independent studies of the Early Growth Genetics (EGG) 2020 (OR = 1.06, 95% CI 0.89-1.27, P = 0.513) and EGG2015 (OR = 1.02, 95% CI 0.97-1.09, P = 0.423). Meta-analysis results further confirmed the reliability of the causal inference. Conclusions The findings indicate that elevated BMI in adults, particularly among middle-aged and elderly populations, increases the risk of developing SSS. In contrast, no causal relationship was observed between childhood BMI and SSS, suggesting that the influence of BMI on SSS susceptibility may predominantly emerge during later life stages. These results highlight the need for targeted public health interventions to address adult obesity as a modifiable risk factor for SSS.