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Parvalbumin Promoter Methylation Altered in Major Depressive Disorder.

ABSTRACT: Aims: To determine the extent of DNA methylation of parvalbumin gene (PVALB) promoter in major depressive disorder (MDD) patients with and without suicide attempt in comparison with healthy controls. Methods: The extracted DNA from dried blood spots of MDD patients (n = 92) including non-suicidal MDD and suicidal-MDD subgroups (n = 45 and n = 47, respectively) and age-matched control subjects (n = 95) was used for DNA methylation analysis at four CpG sites in the promoter sequence of PVALB by pyrosequencing. Results: The PVALB methylation was significantly increased at CpG2 and decreased at CpG4 in the MDD group compared to the control group, while there was no difference between non-suicidal MDD and suicidal-MDD subgroups. A significant inverse correlation of severity of MDD was indicated only for CpG4. Conclusion: This study provides the first evidence of abnormalities of PVALB promoter methylation in MDD and its correlation with MDD severity indicating a role for epigenetics in this psychiatric disorder.

SUBMITTER: Thaweethee-Sukjai B

PROVIDER: S-EPMC6775273 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Parvalbumin Promoter Methylation Altered in Major Depressive Disorder.

Thaweethee-Sukjai Benjamard B Suttajit Sirijit S Thanoi Samur S Dalton Caroline F CF Reynolds Gavin P GP Nudmamud-Thanoi Sutisa S

International journal of medical sciences 20190814 9

Aims: To determine the extent of DNA methylation of parvalbumin gene (PVALB) promoter in major depressive disorder (MDD) patients with and without suicide attempt in comparison with healthy controls. Methods: The extracted DNA from dried blood spots of MDD patients (n = 92) including non-suicidal MDD and suicidal-MDD subgroups (n = 45 and n = 47, respectively) and age-matched control subjects (n = 95) was used for DNA methylation analysis at four CpG sites in the promoter se ...[more]

PMID: 31588185

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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.

Project description:Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of anti-depressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated pro-inflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1?, TNF?, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.

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Parvalbumin Promoter Methylation Altered in Major Depressive Disorder.

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Parvalbumin Promoter Methylation Altered in Major Depressive Disorder.

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