Childhood adiposity affects cardiac structure, function and disease risk in later life: evidence of a causal association

Background and Aims The causal relationship between body mass index (BMI) across developmental stages (from birth through childhood) and cardiac outcomes in later life remains unclear. Using longitudinal Mendelian randomization (MR) analysis, we investigated the causal effects of early-life weight indicators on cardiovascular disease risk and cardiac structure and function. Methods We selected independent genetic instruments (r2 < 0.001) associated with BMI at different developmental stages at genome-wide significance level (p < 5 × 10-8) from large-scale genome-wide association studies. The primary analysis used inverse-variance weighted MR to examine the causal effects on cardiovascular diseases (coronary artery disease, heart failure, atrial fibrillation, and ischemic stroke) and 16 measures of cardiac structure and function. Multiple testing correction was performed using the Benjamini-Hochberg procedure. Results Birth weight showed positive associations with coronary heart disease (OR 1.31 [1.17-1.47]) but negative associations with atrial fibrillation (OR 0.82 [0.75-0.91]). The strongest associations were observed during later childhood (7-8 years), with higher BMI being associated with increased risks of coronary heart disease (OR 1.16 [1.06-1.28]), atrial fibrillation (OR 1.20 [1.12-1.29]), and heart failure (OR 1.42 [1.27-1.59]). For cardiac structure, birth weight was negatively associated with ventricular volumes, while BMI at 7-8 years showed positive associations with these parameters. Mediation analyses revealed that type 2 diabetes and blood pressure partially mediated the effects of BMI on cardiovascular outcomes, with mediation proportions ranging from 18.6% to 65.2%. Conclusion Our findings provide genetic evidence for stage-specific effects of BMI on cardiovascular outcomes, with particularly strong associations during later childhood (7-8 years). The adverse impact of childhood BMI on cardiovascular health is partially mediated through type 2 diabetes and blood pressure, emphasizing the importance of early-life weight management for cardiovascular disease prevention.