Kerang Zhang

Decreased regional homogeneity in insula and cerebellum: A resting-state fMRI study in patients with major depression and subjects at high risk for major depression

Functional disconnectivity during the resting state has been observed in subjects with major depressive disorder (MDD), and in subjects at high genetic risk for major depression during task performance. It is hypothesized that functional impairments in certain brain areas are present in patients with MDD and in their first-degree relatives. To test this hypothesis, an analysis of regional homogeneity (ReHo) of the whole brain was performed on 45 subjects. Compared with the control group, subjects with MDD and those at high risk for MDD exhibited significantly decreased ReHo in the right insula and in the left cerebellum. These abnormalities may play an important role in the pathophysiology of depression.

A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform

BACKGROUND Growing evidence shows that the etiological causes and pathological processes underlying major depressive disorder (MDD) and schizophrenia (SCZ) overlap. Our previous study revealed a strong association between the polymorphism ss178077483 in the miRNA-30e precursor (pre-miR-30e) and the risk of SCZ. We thus hypothesized that this SCZ risk allele at the pre-miR-30e gene also confers risk of MDD. METHODS To explore the relationship between miR-30e ss178077483 and MDD, we conducted an association analyses in 1088 MDD patients and 1102 control subjects from the Han Chinese population. We also determined the effects of miR-30e ss178077483 on the development of P300 event-related potential components induced by an auditory odd-ball task. RESULTS We detected a statistically significant positive association between miR-30e ss178077483 and MDD (allelic P=0.0287; genotypic P=0.0275). Moreover, the P300 latency was associated with miR-30e ss178077483 genotypes and the individuals with the C/T genotype have a longer P300 latency than those carrying the C/C genotype (P=0.009). LIMITATIONS Larger numbers of subjects and different ethnic groups would confirm and strengthen these preliminary findings. CONCLUSIONS To our knowledge, this is the first evidence to suggest that miRNA polymorphisms may play an important role in MDD susceptibility. These findings also imply that certain miRNAs may be involved in the etiology of MDD.

The combined effects of the 5-HTTLPR and 5-HTR1A genes modulates the relationship between negative life events and major depressive disorder in a Chinese population.

BACKGROUND Serotonin transporter (5-HTT) and 5-HT receptor (5-HTR) involved in the neurotransmission of 5-HT may play an important role in the development of major depression disorder (MDD). Several lines of evidence suggested that the gene-environment interaction may confer susceptibility to depression. The aim of this study is to analyze the combined effect of four serotonin-related genes and two environmental factors on MDD in a Chinese population. METHODS This study recruited a total of 401 patients with MDD and 391 age- and gender-matched control subjects. They were all Chinese Han origin. Negative life events and objective social supports were assessed using standard rating scales. Six polymorphisms in the four serotonin-related genes (5-HTT, 5-HTR1A, 5-HTR1B and 5-HTR2A) were selected to detect. The analyses of the gene-environment interactions were performed by the Multifactor Dimensionality Reduction (MDR). RESULTS Allelic associations between patients with MDD and controls were observed for the polymorphism of 5-HTTLPR and for rs6295 at the 5-HTR1A locus. The 5-HTTLPR polymorphism was associated with negative life events on MDD. A three-way interaction between the 5-HTTLPR polymorphism, rs6295 and negative life events on MDD was found in the individuals aged from 20 years to 29 years. In addition, the individuals carrying the L/L genotype of 5-HTTLPR could be susceptible to MDD when exposed to negative life events. CONCLUSIONS The 5-HTTLPR polymorphism may modify the interaction between negative life events and MDD in the Chinese population. To our knowledge, this is the first report on the combined effect for the 5-HTTLPR polymorphism and 5-HTR1A genes on modifying the response to negative life events conferring susceptibility to MDD in the 20-29 year group.

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.

A cis-Phase Interaction Study of Genetic Variants Within the MAOA Gene in Major Depressive Disorder

BACKGROUND The genetic basis of major depressive disorder (MDD) has been explored extensively, but the mode of transmission of the disease has yet to be established. To better understand the mechanism by which the monoamine oxidase A (MAOA) gene may play a role in developing MDD, the present work examined the cis-phase interaction between genetic variants within the MAOA gene for the pathogenesis of MDD. METHODS A variable number tandem repeat (VNTR) and 19 single nucleotide polymorphisms (SNPs) within the gene were genotyped in 512 unrelated patients with MDD and 567 unrelated control subjects among a Chinese population. Quantitative real-time polymerase chain reaction analysis was applied to test the effect of genetic variants on expression of the MAOA gene in MDD. RESULTS Neither the VNTR polymorphism nor seven informative SNPs showed allelic association with MDD, but the cis-acting interactions between the VNTR polymorphism and four individual SNPs were strongly associated with MDD risk, of which the VNTR-rs1465107 combination showed the strongest association (p = .000011). Quantitative real-time polymerase chain reaction analysis showed that overall relative quantity of MAOA messenger RNA was significantly higher in patients with MDD than in control subjects (fold change = 5.28, p = 1.7 × 10⁻⁷) and that in the male subjects carrying the VNTR-L, rs1465107-A, rs6323-G, rs2072743-A, or rs1137070-T alleles, expression of MAOA messenger RNA was significantly higher in the patient group than in the control group. CONCLUSIONS The cis-phase interaction between the VNTR polymorphism and functional SNPs may contribute to the etiology of MDD.

An association study of the serotonin transporter and receptor genes with the suicidal ideation of major depression in a Chinese Han population

Major depression (MD) is a common psychiatric disorder and one of its most serious symptoms is suicidal ideation. Six polymorphisms in four genes related to the serotonin system, including the HTTLPR and HTTVNTR in the SLC6A4 gene, rs6295 in the HTR1A gene, rs11568817 and rs130058 in the HTR1B gene, and rs6313 in the HTR2A gene, were studied in 420 patients with MD to investigate the relationship between these genes and suicidal ideation in MD. An allele association study revealed a significant relationship between rs11568817 and suicidal ideation, while no association was found for any of the other five polymorphisms. A haplotype association study suggested that the rs11568817-rs130058 haplotype of the HTR1B gene is significantly associated with suicidal ideation in MD. No association was found between suicidal ideation and the combined effect of the genes studied using rs11568817 as a conditional marker. Our work indicated that the HTR1B gene might be involved in the development of suicidal ideation in MD among a Chinese Han population.

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.

Evidence of Epistasis Between the Catechol-O-Methyltransferase and Aldehyde Dehydrogenase 3B1 Genes in Paranoid Schizophrenia

BACKGROUND Schizophrenia is a common yet severe psychiatric condition characterized by complex genetic mechanism and diverse clinical presentations. Our previous study indicated that the combined effect of two intronic single nucleotide polymorphisms (SNPs), which are located in the catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 3B1 (ALDH3B1) genes, respectively, conferred genetic risk to paranoid schizophrenia. METHODS To further explore the precise mechanism of the COMT and ALDH3B1 interaction involved in the pathophysiology of schizophrenia, we scanned all possible functional SNPs within these two genes by polymerase chain reaction (PCR)-based genotyping analysis in 540 paranoid schizophrenic patients and 660 control subjects from a Han Chinese population. We also determined the effects of schizophrenia-associated SNPs on the development of psychotic symptoms, P300 event-related potential components induced by an auditory odd-ball task, and gene expression examined by quantitative real-time PCR analysis. RESULTS The major findings of this study were that, among the individuals carrying the rs3751082 A allele in the ALDH3B1 gene, the rs4633 T allele in the COMT gene was associated with susceptibility to paranoid schizophrenia (p = .004), development of hallucination (p = 5.141 E-5), delay of P300 latency in both patients (p = .006) and control subjects (p = .02), and increased expression of the COMT gene in control subjects (p = .002). However, the rs4633 T allele did not show any association in the rs3751082 G/G genotype carriers. CONCLUSIONS These findings provided convincing evidence that epistasis between the COMT and ALDH3B1 genes plays an important role in the pathogenesis of schizophrenia.

Machine learning classifier using abnormal brain network topological metrics in major depressive disorder.

Resting state functional brain networks have been widely studied in brain disease research. However, it is currently unclear whether abnormal resting state functional brain network metrics can be used with machine learning for the classification of brain diseases. Resting state functional brain networks were constructed for 28 healthy controls and 38 major depressive disorder patients by thresholding partial correlation matrices of 90 regions. Three nodal metrics were calculated using graph theory-based approaches. Nonparametric permutation tests were then used for group comparisons of topological metrics, which were used as classified features in six different algorithms. We used statistical significance as the threshold for selecting features and measured the accuracies of six classifiers with different number of features. A sensitivity analysis method was used to evaluate the importance of different features. The result indicated that some of the regions exhibited significantly abnormal nodal centralities, including the limbic system, basal ganglia, medial temporal, and prefrontal regions. Support vector machine with radial basis kernel function algorithm and neural network algorithm exhibited the highest average accuracy (79.27 and 78.22%, respectively) with 28 features (P<0.05). Correlation analysis between feature importance and the statistical significance of metrics was investigated, and the results revealed a strong positive correlation between them. Overall, the current study demonstrated that major depressive disorder is associated with abnormal functional brain network topological metrics and statistically significant nodal metrics can be successfully used for feature selection in classification algorithms.