Dataset Information

Association study of CREB1 with Major Depressive Disorder and related phenotypes.

ABSTRACT: Cyclic AMP response element binding protein (CREB) has been implicated in behavioral models of anxiety and depression, antidepressant response in humans, and suicide. One group reported a female-specific association of the CREB1 gene in early-onset Major Depressive Disorder (MDD), while another found no evidence of association with this phenotype. In this study, we sought to examine the evidence for association of the CREB1 gene to MDD and related phenotypes. We used multivariate structural equation modeling to identify and select twin pairs that scored at the extremes of a latent genetic risk factor shared by MDD, neuroticism, and several anxiety disorders from the Virginia Twin Registry. Using one member from each of these pairs, the resulting sample of 589 cases (including 473 subjects with lifetime MDD) and 539 controls were entered into a 2-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2. Eight SNP markers selected to capture the major allelic variation across the haplotype block containing CREB1 were analyzed for differences between cases and controls. Several markers showed criterion differences between cases and controls in the stage 1 sample with some evidence of sex specific effects. However, none of these markers were significant in stage 2 in either sex individually or combined. Our data suggests that common variations in the CREB1 gene do not appear to increase susceptibility for MDD or related phenotypes.

SUBMITTER: Hettema JM

PROVIDER: S-EPMC2844886 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Association study of CREB1 with Major Depressive Disorder and related phenotypes.

Hettema John M JM An Seon-Sook SS van den Oord Edwin J C G EJ Neale Michael C MC Kendler Kenneth S KS Chen Xiangning X

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20091201 8

Cyclic AMP response element binding protein (CREB) has been implicated in behavioral models of anxiety and depression, antidepressant response in humans, and suicide. One group reported a female-specific association of the CREB1 gene in early-onset Major Depressive Disorder (MDD), while another found no evidence of association with this phenotype. In this study, we sought to examine the evidence for association of the CREB1 gene to MDD and related phenotypes. We used multivariate structural equa ...[more]

PMID: 19194961

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Project description:Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of, a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the 5-HT transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT(1A) binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT(1A) gene (HTR1A: -1019 C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the 5-HT transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene-gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Association study of CREB1 with Major Depressive Disorder and related phenotypes.

Publications

Association study of CREB1 with Major Depressive Disorder and related phenotypes.

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