INTRODUCTION:Metabolomics may identify biological pathways predisposing children to risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in infancy and overweight in early childhood in four European birth cohorts. METHODS:Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood were defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed effect models and controlling the false discovery rate (FDR) at 5%. Additionally, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth. RESULTS:In the MWAS analysis, we identified three and eight metabolites associated with rapid growth and overweight respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, was predictive of rapid growth (p=1.6x10-3). Lower levels of the branched chain amino acid (BCAA) valine (p=8.6x10-6) was predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared to 0.69 and 0.69 respectively for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P<0.05) with rapid growth and overweight respectively. The BCAA leucine, remained associated (1.6x 0-3) with overweight after FDR correction. CONCLUSION:The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understanding of mechanisms involved in postnatal growth. Cholestenone and BCAAs are suggestive of a role of the gut microbiome and nutrient signalling respectively in child growth trajectories. Keywords: Obesity, rapid growth, metabolomics, childhood, cord blood, logistic mixed effect models, random forest classifier.