Chunxia Yang

Disrupted resting-state functional connectivity of the hippocampus in medication-naïve patients with major depressive disorder

BACKGROUND The hippocampus has been reported to exhibit structural and functional alterations in patients with major depressive disorder (MDD). But functional relationships between this area and other regions remain unclear. METHODS Region of interest-based correlation analyses were performed in the resting-state functional magnetic resonance imaging data to examine differences in functional connectivity (FC) of the hippocampus between medication-naïve patients with MDD and healthy adults. Correlation analyses were done between clinical variables and the strength of FC in regions showing group differences. RESULTS Positive FC with the hippocampal-ROIs was seen in bilateral limbic system, subcortical areas, temporal lobe, medial and inferior prefrontal cortex while negative FC was observed in bilateral prefrontal cortex, parietal and occipital cortex and the cerebellum. Group comparison showed impaired functional connections of the hippocampus in MDD, with a lack of negative FC in left hippocampal-ROI to bilateral middle frontal gyrus, as well as decreased negative FC in right hippocampal-ROI to right inferior parietal cortex and the cerebellum. Negative correlations were seen between illness duration and the strength of FC in the prefrontal and parietal cortex. LIMITATIONS An optimized method taking individual variability of hippocampal volume into account is merited for the definition of seed regions and computation of FC. Further studies recruiting subjects with subthreshold depressive symptoms are needed. CONCLUSIONS Abnormal functional relationships between the hippocampus and cortical areas may underlie the pathophysiology of MDD.

Microarray Profiling and Co-Expression Network Analysis of Circulating lncRNAs and mRNAs Associated with Major Depressive Disorder

LncRNAs, which represent one of the most highly expressed classes of ncRNAs in the brain, are becoming increasingly interesting with regard to brain functions and disorders. However, changes in the expression of regulatory lncRNAs in Major Depressive Disorder (MDD) have not yet been reported. Using microarrays, we profiled the expression of 34834 lncRNAs and 39224 mRNAs in peripheral blood sampled from MDD patients as well as demographically-matched controls. Among these, we found that 2007 lncRNAs and 1667 mRNAs were differentially expressed, 17 of which were documented as depression-related gene in previous studies. Gene Ontology (GO) and pathway analyses indicated that the biological functions of differentially expressed mRNAs were related to fundamental metabolic processes and neurodevelopment diseases. To investigate the potential regulatory roles of the differentially expressed lncRNAs on the mRNAs, we also constructed co-expression networks composed of the lncRNAs and mRNAs, which shows significant correlated patterns of expression. In the MDD-derived network, there were a greater number of nodes and connections than that in the control-derived network. The lncRNAs located at chr10:874695-874794, chr10:75873456-75873642, and chr3:47048304-47048512 may be important factors regulating the expression of mRNAs as they have previously been reported associations with MDD. This study is the first to explore genome-wide lncRNA expression and co-expression with mRNA patterns in MDD using microarray technology. We identified circulating lncRNAs that are aberrantly expressed in MDD and the results suggest that lncRNAs may contribute to the molecular pathogenesis of MDD.

The combined effects of the BDNF and GSK3B genes modulate the relationship between negative life events and major depressive disorder

For major depressive disorder (MDD), BDNF and GSK3B are logical candidate genes and an interaction between BDNF polymorphism and negative life events has been observed. Our previous study revealed that a gene-gene interaction among BDNF and GSK3B may confer the risk of MDD. In the present study, we hypothesized a gene-environment interaction between the BDNF-GSK3B combination and negative life events in the risk for developing MDD. To test this hypothesis, we conducted a case-control study in a northern Han Chinese population. A total of 404 patients with MDD and 388 age- and gender-matched control subjects were recruited. Negative life events and objective social supports were assessed using standard rating scales. Three polymorphisms of BDNF and GSK3B genes were identified by sequencing. Gene-environment interactions were analyzed by generalized multifactor dimensionality reduction (GMDR). Under a dominant model, we observed a potential association between the GSK3B rs6782799 and MDD (P=0.07), a significant three-way interaction among BDNF rs6265, GSK3B rs6782799, and negative life events (corrected P-value, 0.011-0.012; cross-validation consistency, 7; prediction error, 0.4349). To our knowledge, this is the first report of evidence that the BDNF-GSK3B interaction may modify the relationship between negative life events and MDD in the Chinese population.

Preliminary comparison of plasma notch-associated microRNA-34b and -34c levels in drug naive, first episode depressed patients and healthy controls

BACKGROUND Major depressive disorder (MDD) is a common debilitating disease of unknown etiology. The expression of miRNA is closely related to depression and efficacy of antidepressant therapy. However, whether Notch-associated miRNAs expressions involved in first-episode of MDD are still unknown. METHODS In this study, the expression levels of Notch1, Hes1 mRNA and 5 miRNAs (miR-369-3p, miR-34b-5p, miR-34c-5p, miR-381 and miR-107) in peripheral blood leukocytes of 32 MDD patients and 32 healthy controls were detected using qRT-PCR method. We also assessed the severity of depressive symptom, suicide risk level, negative life events and event-related potential P300. RESULTS The expression levels of miR-34b-5p (62.49 as the median of cases group and 38.62 as median of control group) and miR-34c-5p (7.17 as the median of cases group and 5.45 as median of control group) in MDD patients were significantly higher than these in control subjects. NOTCH1 gene were significantly lower in MDD patients (5.35 as the median of cases group and 6.80 as median of control group), and was negatively correlated with the expression miR-34c-5p and miR-34b-5p. The expression level of miR-34b-5p and miR-369-3p were significantly lower in patients with suicide idea. N1 latency of P300 were positive correlated with miR-34c-5p, miR-107 and miR-381, and P2 latency of P300 were positive correlated with miR-34c-5p, miR-107 and miR-381. LIMITATIONS The sample size was small and the role of candidate miRNAs in the regulation of Notch1 gene and cognitive function are still need to be further investigated. CONCLUSIONS Differentially Notch-associated miRNAs expressions in peripheral blood might be involved in MDD, and the miR-34b-5p and miR-34c-5p levels in peripheral blood leukocytes are closely related to MDD, suicide idea and cognitive function, further studies with large sample size are warranted to test the feasibility of these miRNAs serving as biomarkers for MDD.

Possible Association of the GSK3β Gene with the Anxiety Symptoms of Major Depressive Disorder and P300 Waveform

Glycogen synthase kinase-3β (GSK3β) may play an important role in the brain of patients with major depressive disorder (MDD); therefore, we investigated whether the GSK3β gene is involved in the etiology of MDD and whether it affects MDD endophenotypes. Three single-nucleotide polymorphisms (SNPs) (rs6438552, rs7633279, and rs334558) were genotyped in 559 MDD patients and 486 healthy controls. To explore quantitative traits of MDD, we analyzed the association of these SNPs with the factor scores of the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAMA). We also determined the effects of these SNPs on the measurement of the P300 wave. Although no significant association between GSK3β SNPs and MDD was found, some genotypes and haplotypes were associated with anxiety symptoms in MDD. The three SNPs were associated with the HAMA total score and with the HAMD anxiety and somatization factor score (p<0.05). Three-locus haplotype analysis showed the C-T-G carriers to have a strong association with the HAMA total score (p=0.032). Moreover, the P300 latency and amplitude were also associated with GSK3β genotypes. The individuals with the T allele genotype, both in rs6438552 and rs7633279, have a longer P300 latency than those carrying the C/C (p=0.04) and A/A genotype (p=0.013). The individuals with the G/G genotype in rs334558 have a lower amplitude than those carrying the A allele genotype (p=0.007). Our findings show, for the first time, that GSK3β polymorphisms may play an important role in MDD endophenotypes, especially in anxiety symptoms.

A combined study of GSK3β polymorphisms and brain network topological metrics in major depressive disorder

GSK3β genotypes may interact with major depressive disorder (MDD) and may have a role in determining regional gray matter volume differences from healthy comparison subjects. However, any associations of GSK3β genotypes with MDD related to abnormal functional brain activity have yet to be elucidated. In the present study, resting state functional brain networks were constructed by thresholding partial correlation matrices of 90 regions. Differences in the network features of GSK3β-rs6438552 genotypes were tested, and a 2×2 analysis of variance was performed to identify the main effects of genotypes, disease status, and their interactions in MDD. Compared with CC carriers, T+ carriers with MDD showed increased nodal centralities in many brain regions-mainly the limbic system, thalamus and parts of the parietal, temporal, occipital, and frontal regions. Decreased nodal centralities predominantly occurred in the sensorimotor area and parts of the frontal, occipital, and temporal lobes. Significant interactions between genotypes and disease status were found in the left thalamus, left superior occipital gyrus, and left inferior parietal lobe. Only altered nodal centrality in the left angular gyrus was negatively correlated with scores on the Hamilton Depression Rating Scale. Our results suggest the GSK3β genotypic effect of rs6438552 and its interaction with disease status may contribute to the altered topological organization of resting state functional brain networks in MDD patients.

Diagnostic value of blood-derived microRNAs for schizophrenia: results of a meta-analysis and validation

There is an increasing interest in searching biomarkers for schizophrenia (SZ) diagnosis, which overcomes the drawbacks inherent with the subjective diagnostic methods. MicroRNA (miRNA) fingerprints have been explored for disease diagnosis. We performed a meta-analysis to examine miRNA diagnostic value for SZ and further validated the meta-analysis results. Using following terms: schizophrenia/SZ, microRNA/miRNA, diagnosis, sensitivity and specificity, we searched databases restricted to English language and reviewed all articles published from January 1990 to October 2016. All extracted data were statistically analyzed and the results were further validated with peripheral blood mononuclear cells (PBMNCs) isolated from patients and healthy controls using RT-qPCR and receiver operating characteristic (ROC) analysis. A total of 6 studies involving 330 patients and 202 healthy controls were included for meta-analysis. The pooled sensitivity, specificity and diagnostic odds ratio were 0.81 (95% CI: 0.75-0.86), 0.81 (95% CI: 0.72-0.88) and 18 (95% CI: 9-34), respectively; the positive and negative likelihood ratio was 4.3 and 0.24 respectively; the area under the curve in summary ROC was 0.87 (95% CI: 0.84-0.90). Validation revealed that miR-181b-5p, miR-21-5p, miR-195-5p, miR-137, miR-346 and miR-34a-5p in PBMNCs had high diagnostic sensitivity and specificity in the context of schizophrenia. In conclusion, blood-derived miRNAs might be promising biomarkers for SZ diagnosis.

Amplitude of low-frequency fluctuations in first-episode, drug-naive depressive patients: A 5-year retrospective study

Despite different treatments and courses of illness, depressive symptoms appear similar in bipolar disorder (BD) and major depressive disorder (MDD), causing BD with an onset of depressive episode being frequently misdiagnosed as MDD, and leading to inappropriate treatment and poor clinical outcomes. Therefore, there is an urgent need to explore underlying neural basis to distinguish BD from MDD. The medical records of 80 first-episode, drug-naïve depressive patients with an initial diagnosis of MDD and illness duration of at least 5 years were reviewed retrospectively for this study. Fourteen bipolar depressed patients with a diagnosis conversion from MDD to BD, 14 patients with diagnosis of MDD, and 14 healthy subjects demographically matched with the BD group, were selected to participate in the study. Firstly, we examined whether there were differences among the three groups in whole brain fALFF during resting state. Secondly, clusters showing group differences in fALFF in any two groups were chosen as regions of interest (ROI) and then correlation between clinical features and fALFF values of ROIs were calculated. The BD group showed increased fALFF in bilateral putamen relative to both the MDD group and controls, while the MDD group exhibited decreased fALFF in left superior frontal gyrus (SFG) relative to both the BD group and controls (p < 0.05, corrected). Positive correlations between abnormality in the putamen and symptom severity were observed (significant for the MDD group, p = 0.043; marginally significant for the BD group, p = 0.060/0.076). These results implicate that abnormalities of key regions in the striatum and prefrontal areas may be trait markers for BD and MDD.

The interaction of miR-34b/c polymorphisms and negative life events increases susceptibility to major depressive disorder in Han Chinese population

BACKGROUND Previous studies have shown that microRNAs(miRNAs) are involved in the pathogenesis of MDD; in particular, miR-34b/c has been implicated in MDD risk and found to exert antidepressant effects. However, the effects of miR-34b/c polymorphisms on MDD risk have not been investigated. METHODS In this study, we evaluated the effect of miR-34b/c gene polymorphisms and their interaction with negative life events in relation to MDD, using data from 381 Han Chinese patients with MDD and 291 healthy volunteers. Allelic, genotypic, haplotypic, and gene-environment associations were analyzed using UNPHASED and SPSS software. RESULTS After discarding data with extremely severe negative life events in our study population, we found an association between rs4938723, rs2187473 polymorphisms and MDD in the dominant models (TC/CC vs. TT, OR=1.45, P=0.027; TC/CC vs. TT, OR=3.32, P=0.030). In haplotype analysis, the C-G haplotype (rs4938723/rs28757623) showed the strongest association with MDD (OR=1.95, P=0.026). Additionally, we found significant gene-environment combination rs4938723 C allele, rs28757623 G allele and high level of negative life events (C-G-HN) was significantly associated with MDD (OR, 3.85; 95% CI, 1.62-9.13). In addition, the combination of (C-C-HN) is of significance (OR, 2.99; 95% CI, 1.36-6.60), indicating that the rs28757623 C allele may contribute to the risk of MDD as well. LIMITATIONS The sample size was small and the role of miR-34b/c polymorphisms for MDD should be assessed using independent samples from other ethnic populations. CONCLUSIONS Our results suggest that miR-34b/c is a susceptibility factor for MDD stratified by negative life events and that rs4938723 is a significant association locus for gene-environment interaction in relation to MDD risk.

The interaction of combined effects of the BDNF and PRKCG genes and negative life events in major depressive disorder

Major depressive disorder (MDD) is a mental disorder that results from complex interplay between multiple and partially overlapping sets of susceptibility genes and environmental factors. The brain derived neurotrophic factor (BDNF) and Protein kinase C gamma type (PRKCG) are logical candidate genes in MDD. Among diverse environmental factors, negative life events have been suggested to exert a crucial impact on brain development. In the present study, we hypothesized that interactions between genetic variants in BDNF and PRKCG and negative life events may play an important role in the development of MDD. We recruited a total of 406 patients with MDD and 391 age- and gender-matched control subjects. Gene-environment interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). Under a dominant model, we observed a significant three-way interaction among BDNF rs6265, PRKCG rs3745406, and negative life events. The gene-environment combination of PRKCG rs3745406 C allele, BDNF rs6265 G allele and high level of negative life events (C-G-HN) was significantly associated with MDD (OR, 5.97; 95% CI, 2.71-13.15). To our knowledge, this is the first report of evidence that the BDNF-PRKCG interaction may modify the relationship between negative life events and MDD in the Chinese population.