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Review
. 2010 Jun;15(6):574-88.
doi: 10.1038/mp.2009.141. Epub 2009 Dec 15.

The CRF system, stress, depression and anxiety-insights from human genetic studies

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Review

The CRF system, stress, depression and anxiety-insights from human genetic studies

E B Binder et al. Mol Psychiatry. 2010 Jun.

Abstract

A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically, variants in the gene encoding the CRF(1) receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In-depth characterization of these variants will likely be important in furthering our understanding of the long-term consequences of adverse experience.

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Figures

Figure 1
Figure 1. The actions of CRF at different levels of the stress response
1- CRF nerve terminal in the median eminence release CRF into the hypothalamo-hypophyseal portal system and stimulate ACTH release from the anterior pituitary. 2- CRF directly stimulates cortisol and cathecholamine synthesis from the adrenal gland 3- CRF stimulates noradrenergic neurons in the locus coeruleus 4- CRF mediates a series of behaviors through actions on cortical and limbic brain regions. 5- CRF transcription is negatively regulated by glucocorticoids in the hypothalamus, but positive regulation has been reported in limbic brain regions.
Figure 2
Figure 2. The genetic organization of the CRHR1 gene encoding CRF1
All representations have been derived from www.hapmap.org. The top panel shows the position of the CRHR1 gene on chromosome 17 (yellow). The second panel shows the 2 mega bases (MB) surrounding the CRHR1 gene (highlighted in yellow) with the position of the neighboring genes (red) and the position of the inversion polymorphism (light blue). The next panel shows the position of the exons and introns of the CRHR1 gene, with the 5’ end of the gene on the left. Below are the SNPs available for this gene in the HapMap project with the linkage disequilibrium (LD) structure for the Caucasian CEU population, as most studies on the genetic of CRF system genes have been performed in Caucasians. LD is represented with the r-squared measure with black squares connecting SNPs in complete LD (r-squared = 1) and white squares connecting SNPs with no LD (s-squared = 0). Shades of grey represent r-squared values between 0 and 1. White dots denote the position of SNPs interacting with child abuse to predict adult depressive symptoms (177, 179) or cortisol response in the combined dexamethasone/CRF test (180, 181). The light blue dot denotes the SNPs interacting with life events to predict suicide attempts (145). Red dots denote SNPs predicting response to antidepressants in patients with anxious depression (174, 175). The orange dot denotes the SNP interacting with life stress to predict heavy drinking (183, 184) and the yellow dot denotes the SNP associated with panic disorders together with a SNP in AVPR1B (143).

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