Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P 5 0.002) and lower brain volume (P 5 0.005)]. The same allele was also associated with higher lean body mass (P 5 0.03) and no difference in height (P 5 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P 5 5.5 3 1026. These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n 5 1729 adolescents), FTO was associated with this shared inverse variance at P 5 1.3 3 1029. Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.