Interaction of early life stress and NAD + /SIRT1 pathway genetic risk promotes depression

A recent study demonstrated that rodents exposed to early life stress (ELS) showed changes in fat tissue composition and exhibited depression-like phenotype. Decreased Sirt1 expression in the reward-related nucleus accumbens (NAc) was a key component of this alteration. Our aim was to translate these findings into humans using a population genetic approach and brain imaging data. We tested the interaction of genetic risk of NAD + /SIRT1 pathway and ELS on depression and investigated whether body fat mediates this interaction effect. We also investigated the effect of the genetic risk and ELS interaction on functional connectivity of the NAc. Our findings suggest that interaction between NAD + /SIRT1 pathway risk and ELS contributes to depression in males (beta = 2.9275, p = 0.0002). Additionally, this interaction influences sex-dependent functional connectivity of the NAc with the middle frontal gyrus and triangular part of the inferior frontal gyrus (p = 0.0139). The observed interaction effect is independent of body fat percentage in adults, indicating that these depressogenic genetic effects are not mediated through adiposity. Overall, these results pave the way for potential therapeutic interventions in depressed male patients with NAD + /SIRT1 risk variants who experienced ELS, regardless of their body fat percentage.