title: HPA axis genetic variation, pubertal status, and sex interact to predict amygdala and hippocampus responses to negative emotional faces in school-age children.
abstract: Accumulating evidence suggests a role for stress exposure, particularly during early life, and for variation in genes involved in stress response pathways in neural responsivity to emotional stimuli. Understanding how individual differences in these factors predict differences in emotional responsivity may be important for understanding both normative emotional development and for understanding the mechanisms underlying internalizing disorders, like anxiety and depression, that have often been related to increased amygdala and hippocampus responses to negatively valenced emotional stimuli. The present study examined whether stress exposure and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predict individual differences in amygdala and hippocampus responses to fearful vs. neutral faces in school-age children (7-12 year olds; N = 107). Experience of more stressful and traumatic life events predicted greater left amygdala responses to negative emotional stimuli. Genetic profile scores interacted with sex and pubertal status to predict amygdala and hippocampus responses. Specifically, genetic profile scores were a stronger predictor of amygdala and hippocampus responses among pubertal vs. prepubertal children where they positively predicted responses to fearful faces among pubertal girls and positively predicted responses to neutral faces among pubertal boys. The current results suggest that genetic and environmental stress-related factors may be important in normative individual differences in responsivity to negative emotional stimuli, a potential mechanism underlying internalizing disorders. Further, sex and pubertal development may be key moderators of the effects of stress-system genetic variation on amygdala and hippocampus responsivity, potentially relating to sex differences in stress-related psychopathology.
authors.affiliation: The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO 63130, United States. Electronic address: david.pagliaccio@wustl.edu.
authors.forename: David
authors.initials: D
authors.lastname: Pagliaccio
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Luby
authors.affiliation: The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO 63130, United States; Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gaffrey
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Belden
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States; Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Botteron
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Harms
authors.affiliation: The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO 63130, United States; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, United States; Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, United States; Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Barch
mesh_terms: D000679:Amygdala / Q000502:physiology*; D001931:Brain Mapping; D002648:Child; D005149:Facial Expression; D000066499:Facial Recognition / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007206:Individuality; D008279:Magnetic Resonance Imaging; D008297:Male; D010913:Pituitary-Adrenal System / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011627:Puberty; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012737:Sex Factors; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: 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
keywords: Amygdala; Childhood; Genetics; Hippocampus; Puberty; Stress