Proteome-wide Mendelian randomization identifies circulating proteins causally associated with childhood obesity

Background Childhood obesity is a major public health problem, affecting one in 5 youths. We aimed to characterize biomarkers for pediatric obesity among circulating proteins using Mendelian randomization (MR). Methods We utilized genome-wide significant cis- protein quantitative trait loci (pQTL) from large proteomic GWAS as instruments for circulating protein levels. Cis -pQTL effects on childhood body mass index (BMI) were retrieved from a European GWAS of 39,620 children. MR Wald ratios were calculated to estimate causal effects of each protein on childhood BMI. Sensitivity analyses, including colocalization and phenome-wide association studies (PheWAS), were performed for the candidate proteins to test for violation of the MR assumptions. Replication analyses were conducted using independent GWAS datasets, complemented by reverse MR and tissue enrichment analyses. Findings Among 535 tested proteins, three colocalized and demonstrated decreasing effects on BMI: endoglin (ENG; MR beta: -0.07, 95% CI [-0.10, -0.04], P = 4.4×10⁻⁵), fatty acid binding protein 4 (FABP4; MR beta: -0.33, 95% CI [-0.50, -0.16], P = 1.3×10⁻⁴), and Nectin-like protein-2 (MR beta: -0.26, 95% CI [-0.37, -0.15], P = 5.45×10⁻⁵). Reverse causation was identified for FABP4, suggesting a compensatory mechanism. Conclusion We identified ENG, FABP4, and Nectin-like protein-2 as potential causal blood biomarkers or drug targets for pediatric obesity.