Peripheral leptin receptor gene network modulates the impact of childhood adversity on mental health disorders.

Psychiatric disorders are highly prevalent and often co-morbid with metabolic syndrome. Exposure to adversity in early life is a risk factor for both metabolic and behavioral problems, modifying leptin metabolism and signaling. Leptin is not only an energy-balance regulator, being also associated with the development of affective disorders. Our objective was to investigate if individual variations in peripheral leptin receptor (LepR) gene network function moderate the effect of childhood adversity on psychopathology. We created expression-based polygenic scores (ePRS) reflecting genetic variations that affect expression of the liver LepR gene network. We investigated the interaction between the LepR-ePRS and early adversity on mental health outcomes, namely anxiety and depression, in childhood (MAVAN) and adolescence (ALSPAC). In both cohorts, there were interaction effects between early adversity exposure and the liver-based LepR-ePRS, in which adversity was associated with depression only in individuals from the high ePRS group. Our findings suggest that exposure to early adversity is associated with mental health problems in children and adolescents. The liver leptin receptor gene network is an important moderator of these effects, and this may be due to individual differences within metabolic and inflammatory pathways represented by this gene network.