Causal Effects of Childhood BMI on Regional Fat Distribution in Adults: A Mendelian Randomisation and Proteomic Mediation Analysis

Childhood obesity is a major global health concern, yet the long-term effects of early-life adiposity on adult fat distribution and underlying biological pathways remain poorly understood. In particular, it is unclear whether childhood BMI differentially influences specific adipose tissue depots and whether circulating proteins mediate these relationships. We conducted a Mendelian randomisation study using genetic instruments for childhood BMI across 12 timepoints from ages 3 to 18 years. Two-sample MR was applied to five MRI-derived adult fat depots (abdominal subcutaneous (ASAT), gluteofemoral (GFAT), visceral (VAT), liver, and pancreatic fat) in UK Biobank. We further implemented a two-step MR framework to assess whether 2,940 circulating plasma proteins (Olink) mediate observed associations, integrating temporal, statistical, and directional evidence across childhood. Genetically predicted higher childhood BMI from approximately age 7 years onwards was associated with increased ASAT and GFAT in adulthood, but showed little evidence of association with visceral, liver, or pancreatic fat, with effects persisting into adolescence. Two-step MR identified 140 proteins influenced by childhood BMI during a developmentally sensitive window, of which seven showed directionally consistent evidence of mediation. These proteins included ACAN, CCL7, and CLIC5 for abdominal subcutaneous fat, and CLIC5, BMP10, CLEC10A, KIT, and IGSF3 for gluteofemoral fat, highlighting partially distinct biological pathways across depots. Childhood BMI exerts depot-specific effects on adult fat distribution, particularly influencing subcutaneous adipose tissue. Circulating proteins provide evidence of potential mediating pathways, supporting the existence of developmentally sensitive biological mechanisms linking early-life adiposity to adult body composition. These findings underscore childhood as a critical period for shaping long-term adipose tissue distribution and highlight potential molecular targets for future intervention strategies.