Stress-System Genes and Life Stress Predict Cortisol Levels and Amygdala and Hippocampal Volumes in Children

Abstract

Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3-5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7-12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3-5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

“…Klengel et al (2013) demonstrated that this G × E is associated with increased risk for stress-related disorders including PTSD and depression. In addition, FKBP5 risk variants have been associated with neuroimaging markers implicated in stress-related disorders, including amygdala and hippocampal volume and reactivity (Fani et al, 2013;Holz et al, 2015;Pagliaccio et al, 2014;White et al, 2012). Several important features of this story are worth highlighting.…”

Stress and depression: old questions, new approaches

“…Larger-scale longitudinal studies of multiple variables are among promising examples (e.g. Waters et al [44], and Washington University investigators [64 ]). The stressdepression field is in the early phases of an exhilarating era of creative integration.…”

Implications of Polymorphisms in the CRHR1 Gene on the Hypothalamic-Pituitary-Adrenal Axis Functioning in Postpartum Depression

“…Conversely, two studies described a protective effect of the presence of TAT copies against depression in individuals with a history of abuse [17,19]. Many factors could explain these discrepancies, such as different types of traumatic events and age of exposure, variability in the severity and comorbidity of mental disorders, interference of other variables such as aminergic systems and possible associations between CRHR1 SNPs and SNPs of other genes [59,60].…”