title: Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function.
abstract: Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college-attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat-related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self-reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear.
authors.affiliation: BRAIN Lab, Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: crdiiorio@wustl.edu.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Di Iorio
authors.affiliation: BRAIN Lab, Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Carey
authors.affiliation: BRAIN Lab, Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Michalski
authors.affiliation: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Nadia S
authors.initials: NS
authors.lastname: Corral-Frias
authors.affiliation: 23andMe, USA.
authors.forename: Emily Drabant
authors.initials: ED
authors.lastname: Conley
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.affiliation: BRAIN Lab, Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA; Neurosciences Program, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA; Molecular Genetics and Genomics Program, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA; Human and Statistical Genetics Program, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: rbogdan@wustl.edu.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
mesh_terms: D000293:Adolescent; D000679:Amygdala / Q000503:physiopathology*; D001007:Anxiety / Q000235:genetics; D001008:Anxiety Disorders / Q000503:physiopathology; D003863:Depression / Q000235:genetics; D003866:Depressive Disorder / Q000503:physiopathology; D004644:Emotions / Q000502:physiology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000502:physiology; D008016:Life Change Events; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology; D011795:Surveys and Questionnaires; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C561839:NR3C2 protein, human
keywords: Amygdala; Anxiety; Cortisol; Depression; Early life stress; Gene; HPA