Evaluating the consequences of childhood adiposity on the human plasma proteome at four timepoints across the lifecourse.

Applying a lifecourse approach using human genetic data, we evaluate the effect of childhood adiposity on the circulating proteome using measurements taken at four key life stages. Using lifecourse Mendelian randomization, we find genetically predicted childhood adiposity to have an effect on 8 proteins measured during childhood (mean age: 9.9 years) including increased circulating TNFSF11 which is involved in T cell-dependent immune responses. Using a mediation framework, we demonstrate that TNFSF11 confers risk of childhood-onset asthma (colocalization posterior probability =88.6%) but not adult-onset asthma (colocalization posterior probability =0.2%), highlighting its putative role as a causal intermediate between adiposity and asthma risk specific to early stages in the lifecourse. Additionally, we find that genetically predicted childhood adiposity has an independent effect on 24 proteins measured during midlife after accounting for adulthood adiposity. Of particular interest is the effect of childhood adiposity on CST6 and NOTCH3 levels in adulthood, which have been found previously to play a role in breast cancer susceptibility.