Depression is thought to arise from a combination of stressful experiences and genetic susceptibility as it has been shown that genes regulating the hypothalamus pituitary adrenal (HPA)-axis, not only modulate physiological stress reactivity, but have likewise been associated with depressive phenotypes. To explore genetic susceptibility, we examined the relation between a validated multilocus genetic profile score (MGPS), comprising genes that regulate HPA axis activity, with mental health outcomes and peripheral biomarkers levels in the context of stressful life experiences. We observed interactions between the MGPS score with traumatic experiences revealing that when individuals were exposed to high levels of trauma, those with lower MGPS, displayed higher stress, depressive, and anxiety symptoms. This study calls attention to the importance of environmental factors when examining genetic susceptibility to mental illnesses. Ultimately, these data suggest that experiences of trauma could potentially "set boundaries" on the impact of genes, overriding genetic predisposition to depression.