CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression.

TitleCRHR1 genotypes, neural circuits and the diathesis for anxiety and depression.
Publication TypeJournal Article
Year of Publication2013
AuthorsRogers, J, Raveendran, M, Fawcett, GL, Fox, AS, Shelton, SE, Oler, JA, Cheverud, J, Muzny, DM, Gibbs, RA, Davidson, RJ, Kalin, NH
JournalMol Psychiatry
Volume18
Issue6
Pagination700-7
Date Published2013 Jun
ISSN1476-5578
KeywordsAnimals, Anxiety, Brain, Depression, Disease Models, Animal, Female, Fluorodeoxyglucose F18, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Macaca mulatta, Male, Polymorphism, Single Nucleotide, Positron-Emission Tomography, Receptors, Corticotropin-Releasing Hormone
Abstract

The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.

DOI10.1038/mp.2012.152
Alternate JournalMol Psychiatry
PubMed ID23147386
PubMed Central IDPMC3663915
Grant ListP30 HD003352 / HD / NICHD NIH HHS / United States
MH081884 / MH / NIMH NIH HHS / United States
P50 MH084051 / MH / NIMH NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 MH081884 / MH / NIMH NIH HHS / United States
MH046729 / MH / NIMH NIH HHS / United States
R01 MH046729 / MH / NIMH NIH HHS / United States
MH084051 / MH / NIMH NIH HHS / United States
P51 OD011106 / OD / NIH HHS / United States

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