Abstract
BACKGROUND: Few studies have investigated molecular biomarkers of specific executive function (EF) skills in children. We aimed to characterise the prospective associations between metabolome and multiple domains of EF using a bidirectional design. METHODS: This study was conducted within a longitudinal birth cohort, the Growing Up in Singapore Towards healthy Outcomes (GUSTO). Circulating levels of 165 metabolites were quantified using a nuclear magnetic resonance based metabolomics platform (n = 457 (∼6yrs) and n = 524 (∼8yrs)). Parent-reported EF was available for 495 children (∼7yrs). Multivariate linear regression was used to assess the metabolite-EF relationships. We examined the role of body composition, dietary factors, and genetics in the metabolite-EF associations. FINDINGS: Higher leucine level (∼6yrs) was associated with poorer EF (∼7yrs, Initiate (P = 0.003) and Working Memory (P = 0.004)). EF (∼7yrs) was not associated with leucine (∼8yrs). Importantly, we found weak evidence for associations of dietary factors (∼5yrs) with leucine (∼6yrs) and EF (∼7yrs). Each copy of C allele in rs1260326 (a leucine-related polymorphism) was associated with higher leucine level and poorer Initiate and Working Memory (P < 0.05). Amongst those with less strongly genetically influenced leucine, inverse association between leucine and cognitive regulation were weaker among those with higher BMI. INTERPRETATION: The observed association between higher leucine level and poorer EF may be determined by genetics and may not be easily amenable to dietary interventions. Further research is needed for validation and to understand mechanisms. FUNDING: Singapore National Research Foundation and Agency for Science, Technology and Research.