Abstract
BACKGROUND: While the relationship between adult obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) is well established, the impact of childhood obesity remains unclear. We aimed to comprehensively characterize the causal effect and genetic relationships of child obesity-related exposures at different ages and MASLD. METHODS: Using summary statistics from large-scale genome-wide association studies of child obesity-related traits and MASLD in European-ancestry populations, we performed linkage disequilibrium score regression and SUPERGNOVA to quantify overall and local genetic correlations, respectively. Univariable Mendelian randomization (UVMR) analysis infers causal relationships. Genomic structural equation modeling (GenomicSEM) and multivariable Mendelian randomization (MVMR) estimated independent genetic correlations and causal effects of each obesity-related trait on MASLD. A two-step Mendelian randomization analysis investigated the mediating pathway from childhood obesity to MASLD through adult obesity. RESULT: We observed a positive genetic correlation between BMI at age 5 years and MASLD ( = 0.45, P -value = 0.01), and a similar correlation for BMI at age 7 ( = 0.44, P -value = 0.044). A significant negative genetic correlation was identified between birth weight and MASLD ( = -0.23, P -value = 4.4 × 10 -8 ). UVMR indicated increased MASLD risk was associated with overall obesity (OR ivw = 1.40, 95% CI = 1.22-1.62) and obesity at age 8 years (OR ivw = 1.34, 95% CI = 1.01-1.78). Birth weight had a protective effect (OR ivw = 0.69, 95% CI = 0.61-0.78). The birth weight effect estimate attenuated to null after collectively adjusting for lifestyle factors in MVMR (OR = 1.05, 95% CI = 0.98-1.12). Mediation analysis showed that this masking effect was mediated by adult obesity. CONCLUSION: These findings suggest that the association between childhood obesity at different ages and MASLD may differ, indicating a contribution of childhood obesity to MASLD risk and confirmed that sustained obesity into adulthood is the mediating pathway.