Article

Effects of the G(-656)A variant on CREB1 promoter activity in a neuronal cell line: interactions with gonadal steroids and stress.

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Molecular Psychiatry (Impact Factor: 15.15). 04/2008; 14(4):390-7. DOI: 10.1038/mp.2008.23
Source: PubMed

ABSTRACT Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position -656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A(-656) allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations.

0 Bookmarks
 · 
71 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Major depressive disorder (MDD) is one of the most severe psychiatric disorders. The objective of this study was to explore the effects of CREB1 gene polymorphisms on risk of developing MDD and the joint effects of gene-environment interactions. Genotyping was performed by Taqman allelic discrimination assay among 586 patients and 586 healthy controls. A significant impact on rs6740584 genotype distribution was found for childhood trauma (P = 0.015). We did not find an association of CREB1 polymorphisms with MDD susceptibility. However, we found a significantly increased risk associated with the interactions of CREB1 polymorphisms and drinking (OR = 11.67, 95% CI = 2.52-54.18; OR = 11.52, 95% CI = 2.55-51.95 for rs11904814; OR = 4.18, 95% CI = 1.87-9.38; OR = 5.02, 95% CI = 2.27-11.14 for rs6740584; OR = 7.58, 95% CI = 2.05-27.98; OR = 7.59, 95% CI = 2.12-27.14 for rs2553206; OR = 8.37, 95% CI = 3.02-23.23; OR = 7.84, 95% CI = 2.93-20.98 for rs2551941). We also noted that CREB polymorphisms combined with family harmony and childhood trauma conferred increased susceptibility for MDD. In conclusion, polymorphisms in the CREB gene may not be independently associated with MDD risk, but they are likely to confer increased susceptibility by interacting with environmental risk factors in the Chinese population.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with the development of MDD in men and women from families identified by probands with recurrent, early-onset MDD (RE-MDD). Individuals in these families are also at increased risk for childhood developmental disorders and late life neurodegenerative disorders. The current study used three-dimensional magnetic resonance microscopy (3D-MRM) to determine the effect of the resulting humanized mutation of the mouse Creb1 gene on the anatomy of the mouse brain. Homozygous mutant mice manifested prominent increases in the volume and surface area of the lateral ventricles, as well as reduced volume of the anterior corpus callosum, compared to age/sex-matched wild-type mice. No significant genotype effects were observed on the volume or surface area of total brain, or several brain regions sometimes observed to be abnormal in human depression, including hippocampus, amygdala, or striatum. These findings suggest that at least some forms of MDD result from abnormal brain development produced by inherited genetic variants. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2013; DOI:10.1002/ajmg.b.32198 · 3.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with MDD in individuals from families with recurrent, early-onset MDD (RE-MDD). In the current study, we explored the effect of the pathogenic Creb1 allele on gene expression in the mouse hippocampus, a brain region that is altered in structure and function in MDD. Mouse whole-genome profiling was performed using the Illumina MouseWG-6 v2.0 Expression BeadChip microarray. Univariate analysis identified 269 differentially-expressed genes in the hippocampus of the mutant mouse. Pathway analyses highlighted 11 KEGG pathways: the phosphatidylinositol signaling system, which has been widely implicated in MDD, Bipolar Disorder, and the action of mood stabilizers; gap junction and long-term potentiation, which mediate cognition and memory functions often impaired in MDD; cardiac muscle contraction, insulin signaling pathway, and three neurodegenerative brain disorders (Alzheimer's, Parkinson's, and Huntington's Diseases) that are associated with MDD; ribosome and proteasome pathways affecting protein synthesis/degradation; and the oxidative phosphorylation pathway that is key to energy production. These findings illustrate the merit of this congenic C57BL/6 recombinant mouse as a model of RE-MDD, and demonstrate its potential for highlighting molecular and cellular pathways that contribute to the biology of MDD. The results also inform our understanding of the mechanisms that underlie the comorbidity of MDD with other disorders. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2014; 165(6). DOI:10.1002/ajmg.b.32257 · 3.27 Impact Factor

Preview

Download
0 Downloads
Available from