Obesity- and age-dependent genetic regulation of the plasma proteome in children and adolescents

The genetic regulation of the plasma proteome has been extensively studied in adult populations, yet protein quantitative trait loci (pQTL) studies in children and adolescents remain largely unexplored. Here, we mapped pQTLs for 178 plasma proteins measured using affinity-based proteomics in 3,853 Danish children and adolescents (44.1% boys; median age of 11.6 years) from the HOLBAEK Study. We aimed to identify context-dependent pQTLs, where genetic variant-protein associations varied across biological contexts such as obesity, puberty, and sex. We further investigated pQTL variation across the lifespan by comparing our findings to pQTL data from UK Biobank. In the HOLBAEK Study, we identified 1,328 independent, genome-wide significant associations for 178 proteins, replicating previously identified pQTLs in adult cohorts. We identified obesity-dependent cis-pQTLs for IL-1ra, TRANCE, and PIgR and found nominally significant evidence for puberty- and sex-dependent genetic differences. Comparative analysis revealed age-dependent differences in cis-pQTLs for 30 proteins between children and adolescents of the HOLBAEK Study (aged 4 to 20 years) and adults from the UK Biobank (aged 40 to 70 years). Through one-sample Mendelian randomization analysis, we identified 70 protein-cardiometabolic trait links at nominal significance, highlighting the potential causal role of proteins in cardiometabolic health in children and adolescents.