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Introduction: Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders, although its underlying genetic mechanism remains unknown. Insulin receptor substrate-1 (IRS-1) is one of the critical downstream molecules in the insulin resistance signaling pathway, linking depression and diabetes. Therefore, we hypothesized that IRS-1 would be a susceptible gene for MDD, and we aimed to examine the genetic association between IRS-1 and MDD. Methods: This case-control study included 583 patients with MDD and 564 controls, and the genotypic and allelic distributions of the IRS-1 gene's four single nucleotide polymorphisms (SNPs) were detected by TaqMan SNP genotyping technology. Of the 583 patients, 191 underwent a further detailed interview about symptom severity and family history of mental illness. The chi-square or t test was used to analyze the data, and analyses were performed using SPSS19.0 software. Results: A haplotype in the 5ʹ-upstream region of IRS-1 consisting of rs13411764 and rs3820926 was a risk factor of MDD. Patients with a family history of mental illness were more likely to have a GG genotype in rs13411764 and a G-T haplotype containing rs13411714-rs3820926. Discussion: The findings imply that the haplotype consisting of rs13411764 and rs3820926 in the upstream of IRS-1 is a risk factor for MDD. This haplotype could affect IRS-1 expression levels, and it is mostly inherited from parents. Thus, the presence of variants in the upstream region of IRS-1 is a risk factor of MDD, and this study could serve as a convincing reference for further studies. [ABSTRACT FROM AUTHOR]

Although lines of evidence demonstrated that cytokines play an important role in the pathogenesis of major depressive disorder (MDD), none of the them have been established as reliable biomarkers. We use our previous whole-genome cRNA microarray data to identify epithelial cell-derived neutrophil-activating peptide 78 (ENA78), the most differentially expressed cytokine in peripheral blood between MDD patients and healthy controls; and then we confirmed the result by the quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) for mRNA and protein level, respectively, in an independent drug-naïve first-episode sample set. In addition, to replicate the role of plasma ENA 78 in MDD, and determine the role of ENA78 on the venlafaxine efficiency, we further detected the plasma ENA78 in another independent 8- week follow-up sample set. We found that both of mRNA and plasma of ENA78 decreased in MDD patients, and displayed much lower after venlafaxine treatment. We also found that venlafaxine non-responders had lower level of peripheral plasma ENA78 prior to treatment than responders. Our findings for the first time provided strong evidence that the ENA78 may play a key role of mediator in pathogenesis of MDD and in the mechanism of vinlafaxine effects on MDD indicating that reduced ENA78 may be a potential biomarker for diagnosing of MDD and predicting of response to venlafaxine. [ABSTRACT FROM AUTHOR]

Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p < 0.001), and that the area under the curve of miR-124 from ROC analysis was 0.762 with a sensitivity of 83.33% and specificity of 66.67% in distinguishing MDD patients from healthy controls. In addition, the expression levels of miR-124 were significantly down-regulated after eight weeks of treatment (p < 0.001). MiRNA target gene prediction and functional annotation analysis indicated that altered miR-124 was involved in affecting some important biological processes and pathways related to MDD. These results provide new information on miR-124 involvement in the biological alterations of MDD and in antidepressant effects. [ABSTRACT FROM AUTHOR]

Background Subsyndromal symptomatic depression (SSD) is a common disease with significant social dysfunction. However, SSD is still not well understood and the pathophysiology of it remains unclear. Methods We classified 48 candidate genes for SSD according to our previous study into clusters and pathways using DAVID Bioinformatics Functional Annotation Tool. We further replicated the result by using real-time Quantitative PCR (qPCR) studies to examine the expression of identified genes (i.e., STAT5b , PKCB1 , ABL1 and NRAS) in another group of Han Chinese patients with SSD (n = 50). We further validated the result by examining PRKCB1 expression collected from MDD patients (n = 20). To test whether a deficit in PRKCB1 expression leads to dysregulation in PRKCB1 dependent transcript networks, we tested mRNA expression levels for the remaining 44 genes out of 48 genes in SSD patients. Finally, the power of discovery was improved by incorporating information from Quantitative Trait (eQTL) analysis. Results The results showed that the PRCKB1 gene expression in peripheral blood mononuclear cells (PBMC) was 33.3% down-regulated in SSD patients (n = 48, t = 3.202, p = 0.002), and a more dramatic (n = 17, 49%) down-regulation in MDD patients than control (n = 49, t = 2.114, p = 0.001). We also identified 37 genes that displayed a strong correlation with PRKCB1 mRNA expression levels in SSD patients. The expression of PRKCB1 was regulated by multiple single nucleotide polymorphisms (SNPs) both at the transcript level and exon level. Conclusions In conclusion, we first found a significant decrease of PRCKB1 mRNA expression in SSD, suggesting PRKCB1 might be the candidate gene and biomarker for SSD. [ABSTRACT FROM AUTHOR]

Rationale: In clinical practice, ketamine, an antagonist of the N-methyl- d-aspartate receptor (NMDAR), is used to alleviate depressive symptoms in patients with major depressive disorder (MDD), especially in those with treatment-resistant depression (TRD). Accordingly, the human gene coding for the 2B subunit of the NMDAR ( GRIN2B) is considered a promising candidate gene for MDD susceptibility. Objectives: The primary aim of this study is to examine whether potentially functional polymorphisms of GRIN2B confer risk for MDD, and second to investigate whether GRIN2B acts as a genetic predictor for TRD in MDD patients. Methods: We enrolled 178 TRD and 612 non-TRD patients as well as 779 healthy controls. Results: Four potentially functional polymorphisms (rs1805502, rs890, rs1806201, and rs7301328) within GRIN2B were genotyped in all participants. The haplotype analysis found significant differences in the distribution of the G-T haplotype between the TRD and control groups (corrected P = 0.007), and the frequency of the G-T haplotype in TRD group was significantly higher than that in the controls (TRD/control ratio 0.31:0.21). Statistically significant differences in allele and genotype frequencies were detected between TRD and non-TRD groups for the rs1805502 polymorphism within GRIN2B. There was a significant allelic association between rs1805502 and TRD with an excess of the G allele in the TRD group, compared to non-TRD group (OR = 1.55, 95 % CI = 1.18-2.05, corrected P = 0.008). Conclusions: These initial findings strengthen the hypothesis that GRIN2B not only confers susceptibility to TRD, but also plays a genetic predictor for TRD in MDD patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Our recent work indicated that low-expression of the anti-apoptotic protein B-cell/lymphoma 2 (Bcl-2) mRNA was observed among untreated major depressive disorder (MDD) patients, and the subsequent altered level of Bcl-2 was found to be close to the antidepressant treatment outcome. The primary aim of this present study was to examine whether a particular gene, encoding Bcl-2 (BCL2) confers risk to MDD, and likewise to investigate whether this gene acts as an indicator of antidepressant treatment outcome. Methods: We enrolled 178 treatment-resistant depression (TRD) and 612 non-treatment-resistant depression (NTRD) patients as well as 725 healthy controls. In total, three selected tagging SNPs (tagSNPs) of BCL2 (rs2279115, rs1801018 and rs1564483) were genotyped to test for possible association. Using TaqMan relative quantitative real-time polymerase chain reaction (PCR), we analyzed leukocytic expression of BCL2 mRNA in 47 healthy subjects. Results: Of the three SNPs, we observed no significant differences in genotype and allele frequencies between the MDD and control groups as well as between the TRD and NTRD groups. However, we found a significant association between the rs2279115C allele and TRD in males (corrected P=0.048) but not in females. Further real-time quantitative PCR analysis in healthy subjects revealed that the rs2279115 polymorphism significantly influenced BCL2 mRNA expression (P=0.03). Limitations: This is a preliminary investigation with relatively small sample size and cross-sectional design. Conclusions: These initial findings strengthen the hypothesis that BCL2 may play an important role in mediating the outcome of antidepressant treatment, a result that may further be confirmed by future genetic studies from large-scale populations that can overcome the limited sample size of this preliminary finding. [Copyright &y& Elsevier]

Background: A growing body of evidence highlights the existence of shared genetic susceptibility to both major depressive disorder (MDD) and bipolar disorder (BD), suggesting some potential genetic overlap between the disorders. Genome-wide association studies have identified consistent association of single nucleotide polymorphisms of the α-1 C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with MDD and BD, suggesting CACNA1C as a promising candidate gene for susceptibility to mood disorders. In the present study, we tested the association of CACNA1C with MDD and BD in Han Chinese. Methods: We genotyped three potentially functional polymorphisms in 635 MDD patients, 286 BD patients and 730 normal, control patients. Results: The genotype frequencies of SNP rs1051375 showed statistically significant differences between the BD and control groups (P=0.005). At the allele level, the difference of G allele frequency of rs1051375 between BD patients and control subjects was also significant (P=0.011; OR=1.30, 95% CI: 1.06–1.58). We found that GG genotype of rs1051375 carriers had a lower age at onset than those with the AG or AA genotype, and the mean±standard deviation ages at onset of GG, AG and AA carriers were 24.04±4.22, 25.76±4.75 and 25.78±4.33 years, respectively. Neither genotype nor allele frequencies of the three polymorphisms were found to be significantly different between the MDD patients and control subjects. Limitations: The relative small sample size in BD group should be considered a limitation of this study. Conclusions: Our initial findings support a potential association of CACNA1C as a genetic risk factor for BD susceptibility. [ABSTRACT FROM AUTHOR]

• A total of 17 miRNAs were screened out to be differentially expressed in medication-naïve MDD patients compared to HC. • miR-374b and miR-10a expression differed between MDD patients and controls. • miRNAs may serve as biomarkers for treatment response in major depressive disorder. Compelling recent evidence suggests that microRNAs (miRNAs) regulate specific mRNA transcripts at the transcriptomic level and coordinately influence complex regulatory networks, which may play a crucial role in the pathogenesis of major depressive disorder (MDD) and the treatment effects of antidepressants. To evaluate the possible involvement of miRNAs in the pathophysiology and therapeutic response of MDD, we conducted a miRNA expression array analysis of the peripheral blood mononuclear cells (PBMCs) of 5 depressed patients and 5 healthy controls (HCs). Subsequently, we chose 2 miRNAs for validation with real-time PCR (RT-PCR) analysis pre- and post-treatment in another group of 25 MDD patients and 25 HCs. In the array, 5 miRNAs were differentially expressed in medication-naïve MDD patients compared to HCs, of which 2 miRNAs were upregulated and 3 were downregulated. Furthermore, in comparison with HCs, MDD patients showed significantly lower expression levels of miR-374b and miR-10a before treatment. After 8 weeks of antidepressant treatment, both miR-374b and the miR-10a expression levels in MDD patients were significantly elevated only in responders. In conclusion, these results indicate the involvement of miR-374b and miR-10a in the biological mechanisms and therapeutic response of MDD, and provide new insights for exploring miRNAs as potential biomarkers for MDD. [ABSTRACT FROM AUTHOR]