Proteome-wide mendelian randomization reveals circulating proteins causally associated with childhood body mass index

Abstract

Abstract 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). We utilized genome-wide significant cis-protein quantitative trait loci (pQTL) from three large adult proteomic GWAS (N total>58,000) and a small childhood proteomic GWAS (N=2,147) as genetic instruments for circulating protein levels. Using two-sample Mendelian randomization, we estimated causal effects of the circulating proteins on childhood body mass index (BMI) in a European GWAS of 39,620 children. MR Wald ratios were calculated to estimate the causal effect of each protein on childhood BMI. Sensitivity analyses testing the MR assumptions included colocalization and phenome-wide association studies (PheWAS). Replication was conducted using independent GWAS datasets, complemented by reverse MR and tissue enrichment analyses. Among 535 tested proteins, three colocalized and demonstrated decreasing effects on BMI per standard deviation increase in their level: 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 cell adhesion molecule 1 (CADMI1; MR beta: -0.26, 95% CI [-0.37, -0.15], P=5.45×10⁻ 5 ). All three proteins showed evidence of colocalization (posterior probability >75%) and were identified using adult proteomic GWAS, given a limited statistical power using the pediatric proteomic GWAS data. Reverse causation was identified for FABP4, suggesting a compensatory mechanism. In conclusion, we identified three circulating proteins as potential blood biomarkers or drug targets for pediatric obesity, warranting further functional validation to elucidate biological mechanisms and assess therapeutic potential.