title: 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.
authors.affiliation: Program in Neuroscience, Washington University in St Louis, St Louis, MO, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pagliaccio
authors.affiliation: Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Luby
authors.affiliation: 1] Program in Neuroscience, Washington University in St Louis, St Louis, MO, USA [2] Department of Psychology, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
authors.affiliation: Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gaffrey
authors.affiliation: Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Belden
authors.affiliation: 1] Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA [2] Department of Radiology, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Botteron
authors.affiliation: Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Harms
authors.affiliation: 1] Program in Neuroscience, Washington University in St Louis, St Louis, MO, USA [2] Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA [3] Department of Psychology, Washington University in St Louis, St Louis, MO, USA [4] Department of Radiology, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Barch
mesh_terms: D000679:Amygdala / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007406:Interview, Psychological; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012463:Saliva / Q000378:metabolism*; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D006854:Hydrocortisone; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C497713:NR3C1 protein, human; C561839:NR3C2 protein, human