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

Applying a lifecourse approach using human genetic data, we sought to evaluate the effect of childhood adiposity on the circulating proteome using measurements taken at three key life stages. We found genetically predicted childhood adiposity to have an effect on 8 proteins measured during childhood (mean age: 9.9 years) including TNFSF11 which is involved in T cell-dependent immune response. Using a mediation framework, we demonstrate that TNFSF11 confers risk of childhood-onset asthma (colocalization posterior probability (PPA)=88.6%) but not adult-onset asthma (PPA=0.2%), highlighting its putative role as a causal intermediate between adiposity and asthma risk specific to early stages in the lifecourse. Additionally, we found that genetically predicted childhood adiposity has an independent effect on 20 proteins measured during midlife after accounting for adulthood adiposity. Replication analyses supported effects of childhood adiposity on CST6 and NOTCH3 which have been found previously to play a role in breast cancer susceptibility.