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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]

Dopamine receptor D2 (DRD2) and catechol- O -methyltransferase (COMT) are important in dopamine system which is proved to be associated with food-anticipatory behavior, food restriction, reward and motivation. This has made them good candidates for anorexia nervosa (AN). The aim of this work is to explore the roles of DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) gene polymorphisms in the susceptibility of AN within the Chinese Han population. We recruited 260AN patients with DSM-IV diagnosis criteria, and 247 unrelated, normal weight controls. DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) were genotyped in all subjects. We found rs1800497 and rs4633 were associated with the susceptibility of AN within the Chinese Han sample, and allele C of rs1800497 was a protective factor. There was a gene–gene interaction between rs1800497 of DRD2 gene and rs4633 of COMT gene. We concluded that rs1800497 and rs4633 play important roles in the AN susceptibility with respect to the Chinese Han population. The gene–gene interaction between DRD2 and COMT contributes to the risk of AN. [ABSTRACT FROM AUTHOR]

Abstract: Emerging evidence from therapeutic trials in humans and animal models suggests that in the treatment of depression, antidepressants play a role by targeting the glutamatergic system. Fluvoxamine is one of the widely used SSRIs which has been considered to target monoamine neurotransmitter reuptake mechanisms. However, whether fluvoxamine has an effect on the glutamate release is still unclear. The present experiment studied the effect of fluvoxamine on presynaptic glutamate release in prelimbic cortex, both in control C57BL/6 mice and chronic restraint stress C57BL/6 mice, and further investigated the mechanism underlying this effect by using patch clamp, on-line fluorimetry, pharmacological approaches combined with other techniques. The results showed that fluvoxamine increased the glutamate release in the depression model mice but it had no effect on the glutamate release in the control mice. The mechanism underlying these effects in depression model mice was that, fluvoxamine firstly activated presynaptic 5-HT3 receptors, which transiently increased the Ca2+ concentration. The increase of Ca2+ concentration via 5-HT3 receptors caused the activation of sigma-1 receptors, which were activated by fluvoxamine. The activation of sigma-1 receptors increased the intrasynaptosomal Ca2+ concentration significantly through the outflow of endoplasmic reticulum calcium and finally activated PKC. These results suggested that fluvoxamine may have a selective effect and different mechanism based on the condition of animal. [Copyright &y& Elsevier]

Previous studies have explored associations between Tumour Necrosis factor-Alpha (TNF-a) polymorphisms and Schizophrenia. Their results were controversial. We conducted a meta-analysis to clarify the association between TNF-a − 308 G/A(rs1800629), −1031T/C(rs1799964), −863C/A(rs1800630) and −857 C/T (rs1799724) polymorphisms and Schizophrenia. All the studies that investigated the association between TNF-a polymorphisms and Schizophrenia published before 15 October 2020 were included in. The literature were comprehensively searched and identified in 2 English databases and 2 Chinese databases. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. For −1031 T/C polymorphism, at the overall analysis, significantly decreased Schizophrenia risk was found in T allele in the allele model (p = 0.006, OR = 0.88) and increased Schizophrenia risk was found in TC + CC genotype in the dominant model (p = 0.005, OR = 1.17). Similarly, the same results were obtained when pooled analyses were included in high-quality studies (allele model: p = 0.005, OR = 0.86; dominant model: p = 0.007, OR = 1.20). In addition, when stratified by ethnicity, the results showed that in allele model, the T allele decreased Schizophrenia risk in East Asian (p = 0.031, OR = 0.90). The association may most likely result from less-credible, rather than from true associations or biological factors on the TNF-a − 1031 T/C polymorphism with Schizophrenia risk. For −1031T/C polymorphism, at the overall analysis, significantly decreased schizophrenia risk was found in T allele in the allele model, and increased schizophrenia risk was found in TC + CC genotype in the dominant model. In allele model, the T allele decreased schizophrenia risk in East Asian when stratified by ethnicity, and in the dominant model, TC + CC genotype increased schizophrenia risk in East Asian. [ABSTRACT FROM AUTHOR]

To examine whether psychological traits (PT) had causal effects on Mouth Ulcers (MU), we applied two-sample Mendelian randomization (MR) to genetics association summary statistics of eleven PT and MU. After the adjustment of outlier variants, genetic correlations and multiple testing, well-being (WB) spectrum PT like life satisfactory (odds ratio [OR] = 0.638 per one standard deviation increment of PT score) had protective effects on MU. Reverse WB traits like neuroticism (OR = 1.60) increased the risk of MU. The lack of well-being characteristics may increase the risk of MU, which highlighted the value of preventive oral care for people who have a reverse mental condition. [ABSTRACT FROM AUTHOR]

Background: 15q11–13 region is one of the most complex chromosomal regions in the human genome. UBE3A is an important candidate gene of autism spectrum disorder (ASD), which located at the 15q11–13 region and encodes ubiquitin-protein ligase E3A. Previous studies about UBE3A gene and ASD have shown inconsistent results and few studies were performed in Chinese population. This study aimed to detect the genetic mutations of UBE3A gene in Chinese Han population with ASD and analyze genetic association between these variants and ASD. Methods: The samples consisted of 192 patients with autism according to the DSM-IV diagnostic criteria and 192 healthy controls. We searched for mutations at coding sequence (CDS) regions and their adjacent non-coding regions of UBE3A gene using the high resolution melting (HRM) and Sanger sequencing methods. We further increased sample size to validate the detected variants using HRM and conducted association analysis between case and control groups. Results: A known single nucleotide polymorphism (T > C, rs150331504) located at the CDS4 and a known 5 bp insertion/deletion variation (AACTC+/−, rs71127053) located at the intron region of the upstream 288 bp of the CDS2 of UBE3A gene were detected using Sanger sequencing method. The ASD samples of case group were 391 for rs71127053, 384 for rs150331504 and 384 healthy controls, which were used to make an association analysis. The results of association analysis suggested that there were no significant difference about the allele and genotype frequencies of rs71127053 and rs150331504 between case and control groups after extending the sample size. Besides, rs150331504 is a synonymous mutation and we compared the secondary structure and minimum free energy (MFE) of mRNA harboring the allele T or C of rs150331504 using RNAfold software. We found that the centroid secondary structure apparently differs along with the polymorphisms of rs150331504 T > C, the results suggested that this variant might change the secondary structure of mRNA of UBE3A gene. We did not detect mutations in other coding regions of UBE3A gene. Conclusions: These findings showed that UBE3A gene might not be a major disease gene in Chinese ASD cases. [ABSTRACT FROM AUTHOR]

Objectives: The identification of the potential molecule targets for subsyndromal symptomatic depression (SSD) is critical for improving the effective clinical treatment on the mental illness. In the current study, we mined the genome-wide expression profiling and investigated the novel biological pathways associated with SSD. Methods: Expression of differentially expressed genes (DEGs) were analysed with microarrays of blood tissue cohort of eight SSD patients and eight healthy subjects. The gene co-expression is calculated by WGCNA, an R package software. The function of the genes was annotated by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results: We identified 11 modules from the 9,427 DEGs. Three co-expression modules (blue, cyan and red) showed striking correlation with the phenotypic trait between SSD and healthy controls. Gene ontology and KEGG pathway analysis demonstrated that the function of these three modules was enriched with the pathway of inflammatory response and type II diabetes mellitus. Finally, three hub genes, NT5DC1, SGSM2 and MYCBP, were identified from the blue module as significant genes. Conclusions: This first blood gene expression study in SSD observed distinct patterns between cases and controls which may provide novel insight into understanding the molecular mechanisms of SSD. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether 12-week moderate-intensity aerobic exercise has beneficial effects on oxidative stress markers in blood and on cognitive functions in patients who have methamphetamine dependence. Serum levels of oxidative stress markers, including total anti-oxidation capability, super oxide dismutase (SOD), catalase (CAT), and methane dicarboxylic aldehyde (MDA), were measured at baseline (all participants) and the 12-week follow-up (methamphetamine-dependent patients). Serum levels of CAT and MDA in methamphetamine-dependent patients ( n  = 68) were higher than those in healthy controls ( n  = 35) at baseline. Furthermore, the international shopping list (ISL) task scores of methamphetamine-dependent patients were significantly lower than those of the controls, indicating verbal memory deficits in methamphetamine-dependent patients. Although there were no significant interactions for all cognitive function scores, aerobic exercise improved the processing speed in methamphetamine-dependent patients. Of interest, aerobic exercise significantly attenuated a spontaneous increase in serum MDA levels in methamphetamine-dependent patients after 12-weeks of abstinence. In conclusion, this study showed that methamphetamine-dependent patients with verbal learning and memory deficits have higher serum levels of MDA, and that a 12-week aerobic exercise program may have beneficial effects on the processing speed as well as blood lipid peroxidation in methamphetamine-dependent patients. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has indicated that dysfunction of miR-124 and target gene regulator of G protein signaling 4 (RGS4) may be involved in the etiology and treatment of major depressive disorder (MDD). However, the molecular mechanisms are not fully understood. This study aimed to investigate whether common genetic variations in these two genes are associated with MDD and therapeutic response to antidepressants in the Chinese population. Methods: Three polymorphisms including rs531564 (a functional single-nucleotide polymorphism [SNP] in MIR124-1), rs10759 (a microRNA-binding site SNP in RGS4), and rs951436 (a promoter SNP in RGS4) were genotyped in 225 Chinese MDD patients and 436 controls. Among the MDD patients, 147 accepted antidepressant treatment for 8 weeks with therapeutic evaluation at baseline, week 2, week 4, week 6, and week 8 using the 17-item Hamilton Rating Scale for Depression. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. Results: No significant association with MDD was discovered in single-SNP analyses. However, by MDR analysis, the three-locus model of gene-gene interaction was the best for predicting MDD risk. In pharmacogenetic study, a significant association was found in genotypic frequencies of rs951436 between the remitter and non-remitter groups (p=0.026, correction p=0.078). For further analysis, the rs951436 heterozygote carriers had threefold probabilities of achieving clinical complete remission (odds ratio =3.00, 95% confidence interval =1.33-6.76, p=0.007, correction p=0.021) as compared with rs951436 homozygotes (AA+CC) after 8 weeks of treatment. Conclusion: An interaction effect of MIR124-1 and RGS4 polymorphisms may play a more important role than individual factors for MDD development. Moreover, RGS4 gene polymorphisms may be associated with antidepressant response among the Han population. [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to explore the possible role of the 5-HT2A-1438G/A polymorphism in the susceptibility to anorexia nervosa (AN) in the Chinese Han population. Methods The -1438G/A polymorphism of 249 female AN patients, 228 matched healthy controls, and 198 trios was genotyped using SNaP shot assay. Psychopathological traits of eating-disordered behaviors in AN subjects were examined using the Chinese version of the Eating Disorder Examination Questionnaire. Results Neither the case-control analysis nor the transmission disequilibrium test revealed significant associations between the -1438G/A polymorphism and AN ( P > .05). However, AA homozygote patients with AN had lower weight and shape concern scores of the EDE-Q6.0 than those of GA heterozygotes ( P < .05). Discussion Our findings suggested that female AN patients with 5-HT2A −1438AA genotype may be characterized by less severe eating-disordered psychopathological traits in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Depression is associated with circadian disturbances in which melanopsin was a key mechanism. Further studies have demonstrated that melanopsin gene variations are associated with some depressive disorders and aberrant light can impair mood through melanopsin-expressing retinal ganglion cells (mRGCs). The goal of this study was to explore the direct relationship between depression and melanopsin. Methods: Adult C57BL/6 male mice were physically restrained for 16 h in a 50-ml polypropylene centrifuge tube and all behavioral tests were performed after CRS treatment. Western blot analysis and immunofluorescence were used to detect melanopsin expression in the retina of C57BL/6 mice. And we observed the change of the electrophysiological function and release of glutamate of mRGCs. Results: The melanopsin expression upregulate in mRGCs of chronic restraint stress (CRS)-treating mice which exhibit depression-like behavior. The frequency of blue light-induced action potentials and light-induced glutamate release mediated by melanopsin also increase significantly. This change of melanopsin is mediated by the CRS-induced glucocorticoid. Conclusions: CRS may induce the depression-like behavior in mice via glucocorticoid-melanopsin pathway. Our findings provide a novel mechanistic link between CRS-induced depression and melanopsin in mice. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate the potential role of antagonistic selection in polygenic diseases: if one variant increases the risk of one disease and decreases the risk of another disease, the signals of genetic risk elimination by natural selection will be distorted, which leads to a higher frequency of risk alleles. Methods: We applied local genetic correlations and transcriptome-wide association studies to identify genomic loci and genes adversely associated with at least two diseases. Then, we used different population genetic metrics to measure the signals of natural selection for these loci and genes. Results: First, we identified 2120 cases of antagonistic pleiotropy (negative local genetic correlation) among 87 diseases in 716 genomic loci (antagonistic loci). Next, by comparing with non-antagonistic loci, we observed that antagonistic loci explained an excess proportion of disease heritability (median 6%), showed enhanced signals of balancing selection, and reduced signals of directional polygenic adaptation. Then, at the gene expression level, we identified 31,991 cases of antagonistic pleiotropy among 98 diseases at 4368 genes. However, evidence of altered signals of selection pressure and heritability distribution at the gene expression level is limited. Conclusion: We conclude that antagonistic pleiotropy is widespread among human polygenic diseases, and it has distorted the evolutionary signal and genetic architecture of diseases at the locus level. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are a class of complex disorders characterized by brain dysfunction with varying degrees of impairment in cognition, emotion, consciousness and behavior, which has become a serious public health issue. The NGFR gene encodes the p75 neurotrophin receptor, which regulates neuronal growth, survival and plasticity, and was reported to be associated with depression, schizophrenia and antidepressant efficacy in human patient and animal studies. In this study, we investigated its association with schizophrenia and major depression and its role in the behavioral phenotype of adult mice. Four NGFR SNPs were detected based on a study among 1010 schizophrenia patients, 610 patients with major depressive disorders (MDD) and 1034 normal controls, respectively. We then knocked down the expression of NGFR protein in the hippocampal dentate gyrus of the mouse brain by injection of shRNA lentivirus to further investigate its behavioral effect in mice. We found significant associations of s2072446 and rs11466162 for schizophrenia. Ngfr knockdown mice showed social and behavioral abnormalities, suggesting that it is linked to the etiology of neuropsychiatric disorders. We found significant associations between NGFR and schizophrenia and that Ngfr may contribute to the social behavior of adult mice in the functional study, which provided meaningful clues to the pathogenesis of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: The relationship between schizophrenia and tumors has sparked much interest and controversy. On the one hand, the health of patients with schizophrenia is affected by a variety of risk factors associated with cancer development, such as smoking, alcohol, and drug abuse. On the other hand, early investigations have found that patients with schizophrenia have a lower cancer incidence than the overall population. This phenomenon has prompted new theories on the processes underlying the protective effect. To explore the connection between schizophrenia and tumors, we used two-sample Mendelian randomization and GWAS meta-analysis methods on the GWAS summary data to assess potential genetic links between schizophrenia and 13 cancers. It was revealed that schizophrenia may lead to an increased risk of breast, ovarian, and thyroid cancers. Furthermore, the thyroid-stimulating hormone level is impacted by schizophrenia, which may further affect the estrogen and thyroid hormone levels. Meanwhile, based on our results, AS3MT, SFXN2, and PCCB may be potential biomarkers for preventing breast and thyroid cancers in patients diagnosed with schizophrenia. Therefore, we suggest that patients with schizophrenia should pay close attention to early risk warnings for breast, ovarian, and thyroid cancers. The causal relationship between cancer and Schizophrenia (SCZ) remains controversial. Some researchers have found that SCZ is a cancer-preventive factor in cohort studies or meta-analyses, whereas others have found the opposite. To understand more about this issue, we used two-sample Mendelian randomization (2SMR) on available GWAS summary results to evaluate potential genetic connections between SCZ and 13 cancers. We discovered that the genetic susceptibility to schizophrenia lead to an increasing risk of breast cancer (odds ratio [OR] per log-odds increase in schizophrenia risk: 1.049, 95% confidence interval [CI]:1.023–1.075; p = 0.00012; FDR = 0.0017), ovarian cancer (OR, 1.326; 95% CI, 1.267–1.387; p = 0.0007; FDR = 0.0045), and thyroid cancer (OR, 1.575; 95% CI, 1.048–2.365; p = 0.0285; FDR = 0.123). Secondly, we performed a meta-analysis based on the GWAS summary statistics of SCZ and the three significant cancers. Next, we associated genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quantitative trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, we identified 114 shared loci and 437 shared genes in three groups, respectively. Functional enrichment analysis shows that the most enriched biological pathways are related to epigenetic modification. In addition, we noticed that SCZ would affect the level of thyroid-stimulating hormone (OR, 1.095; 95% CI, 1.006–1.191; p = 0.0354; FDR = 0.177), which may further affect the level of estrogen and the risk of the above three cancers. In conclusion, our findings under the 2SMR assumption provide crucial insights into the risk-increasing effect of SCZ on three cancers' risk. Furthermore, these results may provide insights into understanding the genetic predisposition and underlying biological pathways of comorbid SCZ and cancers. [ABSTRACT FROM AUTHOR]

Background: Cognitive training may contribute to the ability to maintain cognitive function in healthy elderly adults. Whether genotype modifies training effects remains unknown.Objective: Assess influence of APOE on cognitive function over time in community-dwelling elderly adults participating in multi-domain cognitive training.Methods: Healthy individuals ≥70 years of age were screened from one urban community in Shanghai. 145 healthy Chinese older adults met inclusion criteria and were assigned to intervention (n = 88) or control (n = 57) groups. Multi-domain cognitive training involved 24 sessions of different content taking place over 12 weeks. Neuropsychological testing was administered at baseline, immediately after training, six months and twelve months post-intervention; composite measures of cognitive function were identified via factor analysis.Results: Three factors explained the majority of variance in function (verbal memory, processing speed, executive function). The intervention attenuated 12-month declines in processing speed, regardless of APOE genotype (p = 0.047). Executive function declined in APOEɛ4 carriers over 12 months, regardless of intervention (p = 0.056). There was a significant interaction after 12 months where intervention ɛ4 carriers had better processing speed than ɛ4 controls (p = 0.003). Intervention ɛ2 carriers had better executive function immediately after training (p = 0.02) and had better verbal memory 6-months post-intervention (p = 0.04). These effects remained significant after false-discovery rate correction.Conclusion: Multi-domain cognitive training reduces declines in processing speed over time. APOEɛ4 is associated with reductions in executive function over time, and training may attenuate ɛ4-associated declines in processing speed. APOEɛ2 carriers may also benefit from training, particularly on measures of executive function and verbal memory. [ABSTRACT FROM AUTHOR]

Background: Genetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS. Methods: Literature was searched in multiple databases including PUBMED, COCHRANE and WEB OF SCIENCE up to July 2014. The number of the genotypes for DRD2/ANKK1 TaqIA in the TS and control subjects was extracted and statistical analysis was performed using Review Manager 5.0.16 and Stata 12.0 software. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were utilized to calculate the risk of TS with DRD2/ANKK1 TaqIA. Stratified analysis based on ethnicity was also conducted. Results: 523 patients with TS, 564 controls and 87 probands plus 152 relatives from five published studies were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the DRD2/ANKK1 TaqIA A1 allele were 1.69 (95%CIs = 1.42-2.00) in the fixed-effect model and 1.66 (95%CIs = 1.33-2.08) in the random-effects model. Stratification by ethnicity indicated the TaqIA A1 allele was significantly associated with TS in Caucasians (fixed-effect model: OR=1.75, 95%CI = 1.43-2.16; random-effect model: OR=1.69, 95%CI = 1.25-2.28) and in Asians (OR=1.54, 95%CI = 1.12-2.10). Meta-analysis of the A1A1 vs. A2A2 (homozygous model), A1A2 vs. A2A2 (heterozygous model) and A1A1+A1A2 vs. A2A2 (dominant model) of this polymorphism revealed a significant association with TS in overall populations and Caucasians. Conclusions: This meta-analysis suggested that the DRD2/ANKK1 TaqIA polymorphism might contribute to TS susceptibility, especially in Caucasian population. However, further investigation with a larger number of worldwide studies should be conducted to verify the association. [ABSTRACT FROM AUTHOR]

• There is a significant shared genetic basis between SCZ and cigarette and cannabis smoking (SCZ_SMO) which consisted of 8.6% of SCZ heritability. • At the significance threshold of p <5 × 10−8, 20 loci were significantly associated with SCZ_SMO, which had a heritability of 0.03. • Brain expression level of NCAM1, as well as other genes involved in neuron and dendritic spinal head, was positively associated with SCZ_SMO. • SCZ_SMO has a positive genetic association with both reverse mental and physical conditions, such as social deprivation, lifestyle problems, pregnancy loss, ADHD, etc. Confirming the existence and composition of the shared genetic basis of Schizophrenia and cannabis and cigarette smoking has critical values for the clinical prevention and intervention of psychosis. To achieve this goal, we leveraged Genome-Wide summary statistics of Schizophrenia (n = 99,934), cigarette smoking (n = 518,633) and cannabis usage (n = 162,082). We applied Causal Analysis Using Summary Effect Estimates (CAUSE) and genomic structural equation modeling (GenomicSEM) to quantify the contribution of a common genetic factor of cannabis and cigarette smoking and schizophrenia (referred to as SCZ_SMO), then identified genome-wide loci that made up SCZ_SMO. We estimated that SCZ_SMO explained 8.6% of Schizophrenia heritability (Z score <-2.5 in CAUSE, p <10−20 in Genomic SEM). There were 20 independent loci showing association with SCZ_SMO at the genome-wide threshold of p <5 × 10−8. At the top locus on chromosome 11, fine-mapping identified rs7945073 (posterior inclusion probability =0.12, p = 2.24 × 10−32) as the top risk variants. Gene-level association and fine-mapping highlighted NCAM1, PHC2, and SEMA6D as risk genes of SCZ_SMO. Other risk genes were enriched in cortex, neuron, and dendritic spines (adjusted p <0.05). SCZ_SMO showed significant positive correlation (p <10−6) with the genetic risk of attention deficit hyperactivity disorder (r = 0.50), lifestyle problems (r = 0.83), social deprivation (r = 0.58) and all-cause pregnant loss (r = 0.60). Our result provided new evidence on the shared genetic basis model for the association between Schizophrenia and smoking and provided genetic and biological insights into their shared mechanism. [ABSTRACT FROM AUTHOR]

Rationale Traf2- and Nck-interacting kinase (TNIK), a member of germinal center kinase (GCK) family, has been implicated as a risk factor in schizophrenia and bipolar disorder as well as the action of antipsychotics. TNIK is an essential activator of Wnt/β-catenin signaling pathway which has been identified involved in the mechanism underlying the effects of antipsychotics. Thus, the effects of TNIK on antipsychotics may be achieved by influencing Wnt/β-catenin signaling pathway proteins. Objectives and methods In the current study, the effects of up- or downregulated TNIK on β-catenin, T-cell factor 4 (TCF-4), glycogen synthase kinase-3β (GSK3β), and phosphorylated GSK3β (p-GSK3β) were examined in the human glioma U251 cells. Then, we observed the effects of antipsychotics (clozapine and risperidone) on the above proteins and evaluated the role of differentially expressed TNIK on antipsychotic-treated cell groups. Results The result showed that clozapine treatment decreased β-catenin and TCF-4 levels in U251 cells, and risperidone had the similar effects on β-catenin and p-GSK3β. The downregulated TNIK using siRNA impeded the regulation of antipsychotics on Wnt pathway proteins via increasing the expression levels of TCF-4, β-catenin, or p-GSK3β, whereas the upregulated TNIK made no significant change. Conclusions The influence of TNIK on the effects of antipsychotics may be partly through Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Background: About 20–40 % of autistic people experience a phenomenon of regression. Retinol binding protein 4 (RBP4) plays an important role as an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis. Abnormal fatty acid metabolism and lipid mediators have been reported to be related to the etiological mechanism in autism, and amelioration of impaired lipid metabolism can be recognized as a treatment strategy for autism. The purpose of this study is to explore the relationship between RBP4, lipids, and the autistic regression phenomenon, and to discuss their potentials as biomarkers for the autistic regression phenomenon. Methods: A total of 60 autistic individuals (18 with regression phenomenon, 42 without regression phenomenon) (ASD group) and 36 healthy controls were enrolled in this case-control study. The levels of RBP4, total cholesterol (TC), high-density lipoprotein (HDLC), low–density lipoprotein (LDLC), and triglyceride (TG) were measured. Childhood Autism Rating Scale (CARS) is used to assess the severity of autism. Ethical measures were performed in compliance with the current Declaration of Helsinki and written informed consent was obtained from the parents before enrollment of the children and adolescents. Results: Compared with control subjects, autistic individuals had lower levels of TC (P = 0.007), RBP4 (P = 0.001), and HDLC (P = 0.027). The levels of RBP4 in ASD group were positively correlated with TG (r = 0.355, P = 0.005), HDLC (r = 0.257, P = 0.047), TG/TC (r = 0.376, P = 0.003) and TG/LDLC (r = 0.363, P = 0.004), and were negatively correlated with CARS (r=-0.296, P = 0.003). Further logistic regression demonstrated that decreased RBP4 concentration was associated with the presentation of the autistic regression phenomenon even after the adjustment of the potential confounding factors. Conclusions: Serum RBP4 is associated with the autistic regression phenomenon and the severity of ASD. Further studies are needed to expound whether decreased RBP4 participates in the development of the autistic regression phenomenon. [ABSTRACT FROM AUTHOR]

Clinical high-risk psychosis (CHR-P)1 refers to a heterogeneous state where patients exhibit psychotic syndromes such as hallucination and delusion not reaching the diagnostic criteria, with the ability of self-reasoning and help-seeking partially maintained. Thus, blood transcriptome is valuable to CHR-P's clinical intervention, where treatment choices are dependent on the objective evaluation of symptom severity and conversion risk.9 In addition, our symptom association model also reflected the underlying biological mechanism, such as downregulation of synaptic vesicle recycling during CHR-P progression. Methods To evaluate whether blood RNA could serve as CHR-P biomarkers, we collected blood samples of patients with CHR-P from the Shanghai at-risk psychosis (SHARP) longitudinal cohort7 and applied RNA sequencing. Peripheral transcriptome of clinical high-risk psychosis reflects symptom alteration and helps prognosis prediction. [Extracted from the article]

Background: Observational studies have identified various associations between neuroimaging alterations and neuropsychiatric disorders. However, whether such associations could truly reflect causal relations remains still unknown. Results: Here, we leveraged genome-wide association studies (GWAS) summary statistics for (1) 11 psychiatric disorders (sample sizes varied from n = 9,725 to 1,331,010); (2) 110 diffusion tensor imaging (DTI) measurement (sample size n = 17,706); (3) 101 region-of-interest (ROI) volumes, and investigate the causal relationship between brain structures and neuropsychiatric disorders by two-sample Mendelian randomization. Among all DTI-Disorder combinations, we observed a significant causal association between the superior longitudinal fasciculus (SLF) and the risk of Anorexia nervosa (AN) (Odds Ratio [OR] = 0.62, 95 % confidence interval: 0.50 ~ 0.76, P = 6.4 × 10− 6). Similar significant associations were also observed between the body of the corpus callosum (fractional anisotropy) and Alzheimer's disease (OR = 1.07, 95 % CI: 1.03 ~ 1.11, P = 4.1 × 10− 5). By combining all observations, we found that the overall p-value for DTI − Disorder associations was significantly elevated compared to the null distribution (Kolmogorov-Smirnov P = 0.009, inflation factor λ = 1.37), especially for DTI − Bipolar disorder (BP) (λ = 2.64) and DTI − AN (λ = 1.82). In contrast, for ROI-Disorder combinations, we only found a significant association between the brain region of pars triangularis and Schizophrenia (OR = 0.48, 95 % CI: 0.34 ~ 0.69, P = 5.9 × 10− 5) and no overall p-value elevation for ROI-Disorder analysis compared to the null expectation. Conclusions: As a whole, we show that SLF degeneration may be a risk factor for AN, while DTI variations could be causally related to some neuropsychiatric disorders, such as BP and AN. Also, the white matter structure might have a larger impact on neuropsychiatric disorders than subregion volumes. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) and obsessive–compulsive disorder (OCD) exhibit a high co-morbidity rate, similar symptoms, and a shared genetic basis. However, an understanding of the specific underlying mechanisms of these commonalities is currently limited. Here, we collected Genome-Wide Association Analysis results for AN and OCD, and obtained genes hit by the top SNPs as the risk genes. We then carried out an integrative coexpression network analysis to explore the convergence and divergence of AN and OCD risk genes. At first, we observed that the AN risk genes were enriched in coexpression modules that involved extracellular matrix functions and highly are expressed in the postnatal brain, limbic system, and non-neuronal cell types, while the OCD risk genes were enriched in modules of synapse function, the prenatal brain, cortex layers, and neurons. Next, by comparing the expressions from the eating disorder and OCD postmortem patient brain tissues, we observed both disorders have similar prefrontal cortex expression alterations influencing the synapse transmission, suggesting that the two diseases could have similar functional pathways. We found that the AN and OCD risk genes had distinct functional and spatiotemporal enrichment patterns but carried similar expression alterations as a disease mechanism, which may be one of the key reasons they had similar but not identical clinical phenotypes. [ABSTRACT FROM AUTHOR]

Abstract: This case–control study enrolled 578 obsessive–compulsive disorder (OCD) patients and 649 controls and genotyped rs10491734, rs2228622, rs301430 and rs301443 to replicate association of the SLC1A1 gene with OCD in ethnic Han Chinese. The G-A-C-G and G-G-T-C haplotypes were found to be significantly associated with OCD in overall samples, male samples and female samples. [Copyright &y& Elsevier]

Background: . The development of depressive symptoms (DSs) is a complex process caused by both genetic and environmental factors. CEND1 gene coordinates cell division, differentiation and maturation of neural precursor cells, which affects brain structure and function. Our study investigated whether CEND1 was a genetic factor for DSs, particularly under negative life events.Methods: . 272 freshmen with DSs and 467 healthy controls were recruited via the Center for Epidemiologic Studies Depression Scale (CES-D). The adolescent Self-rating Life Event Checklist (ASLEC) was adopted to assess stressful life events during the past 12 months. Two SNPs (rs7946354, rs6597982) within the CEND1 gene were genotyped using Agena MassARRAY iPLEX technology. We combined generalized multifactor dimensionality reduction (GMDR) with RStudio programming to assess the direct association and gene-environment interaction (G × E).Results: . Rs7946354 was associated with DSs in an overdominant model (GT vs. GG+TT). In addition, both rs7946354 and rs6597982 had considerable impacts on negative life events. GMDR showed a statistical G × E that the AG genotype of rs6597982 and GT genotype of rs7946354 contribute to the maximum risk of DSs under high negative life events.Limitations: . Only two single nucleotide polymorphisms (SNPs) were examined. Verification studies with bigger sample size and more varied demographic background information could be adopted to further support the generalization of these findings.Conclusions: .CEND1 can potentially cause high sensitivity to life events and affect DSs especially in the presence of negative life events, which contribute to the field of depression prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: Nucleus Accumbens (NAc) is a vital brain region for the process of reward and stress, whereas microRNA plays a crucial role in depression pathology. However, the abnormality of NAc miRNA expression during the stress-induced depression and antidepressant treatment, as well as its biological significance, are still unknown.Methods: We performed the small RNA-sequencing in NAc of rats from three groups: control, chronic unpredictable mild stress (CUMS), and CUMS with an antidepressant, Escitalopram. We applied an integrative pipeline for analyzing the miRNA expression alternation in different model groups, including differential expression analysis, co-expression analysis, as well as a subsequent pathway/network analysis to discover both miRNA alteration pattern and its biological significance.Result: A total of 423 miRNAs were included in analysis.18/8 differential expressing (DE) miRNA (adjusted p < 0.05, |log2FC| > 1) were observed in controls Vs. depression/depression Vs. treatment, 2 of which are overlapping. 78% (14/18) of these miRNAs showed opposite trends of alteration in stress and treatment. Two micro RNA, miR-10b-5p and miR-214-3p, appeared to be hubs in the regulation networks and also among the top findings in both differential analyses. Using co-expression analysis, we found a functional module that strongly correlated with stress (R = 0.96, P = 0.003), and another functional module with a moderate correlation with anhedonia (R = 0.89, P = 0.02). We also found that predicted targets of these miRNAs were significantly enriched in the Ras signaling pathway, which is associated with both depression, anhedonia, and antidepressant treatment.Conclusion: Escitalopram treatment can significantly reverse NAc miRNA abnormality induced by chronic stress. However, the novel miRNA alteration that is absent in stress pathology also emerges, which means that antidepressant treatment is unlikely to bring miRNA expression back to the same level as the controls. Also, the Ras-signaling pathway may be involved in explaining the depression disease etiology, the clinical symptom, and treatment response of stress-induced depression. [ABSTRACT FROM AUTHOR]

Abstracts Although many major breakthrough had identificated potential susceptibility genes for schizophrenia, the aetiology of schizophrenia is still unknown. In the present study, we focused on the N -methyl-Daspartate receptors related genes nitric oxide synthase 1 adaptor gene ( NOS1AP ), disrupted in schizophrenia 1 gene ( DISC1 ), d -amino acid oxidase activator gene ( DAOA ), and glycogen synthase kinase 3-beta gene ( GSK3B ). A family-based genetic association study (459 Han Chinese subjects in 153 nuclear families) using 3 single nucleotide polymorphisms in NOS1AP , 2 in DISC1 , 1 in DAOA and 1 in GSK3B was conducted. We found rs12742393 have just positive trend with schizophrenia (SCZ) (p = 0.07) after FDR correction. NOS1AP mRNA and serum levels were significantly elevated in SCZ patients (p < 0.001; p < 0.001) compared with healthy control. However, expression Quantitative Trait Loci (eQTL) analysis have demonstrated that rs12742393 genotype were not significantly associated with the NOS1AP mRNA expression. GMDR identified a significant seven-locus interaction model involving ( NOS1AP -rs348624, rs12742393, rs1415263, DISC1 -rs821633, rs1000731, DAOA -rs2391191and GSK3B - rs6438552) with a good testing accuracy (0.72). Our finding suggested statistically significant role of interaction of NOS1AP , DISC1 , DAOA , and GSK3B polymorphisms ( NOS1AP -rs348624, rs12742393, rs1415263, DISC1 -rs821633, rs1000731, DAOA -rs2391191and GSK3B -rs6438552) in EOS susceptibility. [ABSTRACT FROM AUTHOR]

Background: Recent research findings suggest that BDNF and BDNF signaling pathways participate in the development of major depressive disorder. Mitogen-activated extracellular signal-regulated kinase (MEK) is the most important kinase in the extracellular signal-regulated kinase pathway, and the extracellular signal-regulated kinase pathway is the key signaling pathway of BDNF, so it may play a role in development of depressive disorder. The aim of this study is to investigate the association between polymorphisms of the MAP2K1 (also known as MEK) gene and depressive disorder.Results: Three single nucleotide polymorphisms (SNPs), were significantly associated with depressive disorder: rs1549854 (p = 0.006), rs1432441 (p = 0.025), and rs7182853 (p = 0.039). When subdividing the sample by gender, two of the SNPs remained statistically associated with depressive disorder in females: rs1549854 (p = 0.013) and rs1432441 (p = 0.04).Conclusion: The rs1549854 and rs1432441 polymorphisms of the MAP2K1 gene may be associated with major depressive disorder, especially in females. This study is the first to report that the MAP2K1 gene may be a genetic marker for depressive disorder. [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]

Introduction The homo sapiens nuclear receptor subfamily 4, group A ( NR4A2 ) genetic variation has been implicated as a risk factor for Parkinson's disease (PD). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-analysis to quantify the impact of NR4A2 variation on the risk of PD. Methods All eligible case–control studies published up to June 2016 by searching Pubmed, OVID, EBSCO, PsycINFO, ISI Web of Knowledge, Chinese Biomedical Literature Database and China Academic Journals Database were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of the association in fixed- or random-effects model. Results Eighteen studies reported 24 genetic variants with a total of 6150 cases and 5919 controls were included. Twelve studies for NR4A2 rs35479735 polymorphism and 4 studies for rs12803 were available for meta-analysis. A significant association was observed for rs35479735 under the homozygous model (OR = 1.31, 95% CI: 1.10–1.56, P = 0.003), whereas no significant association for rs12803 was detected. In subgroup analysis stratified by ethnicity, age onset and familial history, we found no significant association except one in sporadic PD subgroup under the recessive (OR = 3.30, 95% CI: 1.23–8.84, P = 0.02) and homozygous model (OR = 3.43, 95% CI: 1.26–9.33, P = 0.02) for rs35479735. Conclusion The study comprehensively evaluated the association of NR4A2 variation with PD, and the results failed to demonstrate that the NR4A2 polymorphisms significantly associated with PD except for rs35479735, suggesting that more studies are needed to elucidate if NR4A2 is a risk of PD. [ABSTRACT FROM AUTHOR]

Background: Subsyndromal symptomatic depression (SSD) is a subtype of subthreshold depressive and can lead to significant psychosocial functional impairment. Although the pathogenesis of major depressive disorder (MDD) and SSD still remains poorly understood, a set of studies have found that many same genetic factors play important roles in the etiology of these two disorders. Nowadays, the differential gene expression between MDD and SSD is still unknown. In our previous study, we compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD and matched healthy controls (8 subjects in each group), and finally determined 48 gene expression signatures. Based on these findings, we further clarify whether these genes mRNA was different expressed in peripheral blood in patients with SSD, MDD and healthy controls (60 subjects respectively) Method: With the help of the quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR), we gained gene relative expression levels among the three groups. Results: We found that there are three of the forty eight co-regulated genes had differential expression in peripheral blood among the three groups, which are CD84, STRN, CTNS gene (F = 3.528, p = 0.034; F = 3.382, p = 0.039; F = 3.801, p = 0.026, respectively) while there were no significant differences for other genes. Conclusion: CD84, STRN, CTNS gene may have significant value for performing diagnostic functions and classifying SSD, MDD and healthy controls. [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]

GABA system genes have been implicated in neurotrophy and neurogenesis, which play pivotal roles in an individual's variation in vulnerability to amphetamine addiction or amphetamine-induced psychosis (AIP). We hypothesized that common genetic variants in the GABA system genes may be associated with amphetamine-induced psychotic disorder. In our study, thirty-six single nucleotide polymorphisms (SNPs) within the GABA system genes were genotyped in 400 amphetamine-induced psychotic disorder patients and 400 amphetamine use disorders patients (AUP) (not including those categorized as psychosis) in the Han Chinese population. In this study, 51.88% of the Han Chinese amphetamine-type substance use disorder patients met the criteria of amphetamine-induced psychotic disorder, and 79.5% amphetamine-induced psychotic disorder patients had auditory hallucinations, while 46.5% had delusions of reference. The allele frequency of rs1129647 showed nominal association with AIP in the Han Chinese population ( P = 0.03). Compared with AUP group patients, T allele frequency of AIP group patients was significantly increased. The adjustment for age and gender factors in the AIP and AUP patients was executed using unconditional logistic regression under five inheritance models. The genotype frequency of rs1129647 showed nominal association with AIP in the log-additive model ( P = 0.04). The genotype frequency of rs2290733 showed nominal association with AIP in the recessive model ( P = 0.04). Compared with female AIP patients, male patients were more likely to have the CC genotype of rs17545383 ( P = 0.04). Moreover, we determined that more male patients carried the T allele of rs2290733 in the AIP group ( P = 0.004). Unfortunately, the significant differences did not survive Benjamini-Hochberg false discovery rate correction (adjusted P > 0.05). No association between the SNPs of the GABA system genes and amphetamine-induced psychotic disorder risk was identified. No haplotype of the GABA system genes affected amphetamine-induced psychotic disorder risk. This report describes the first association study between the GABA system genes and amphetamine-induced psychotic disorder in the Han Chinese population. Our data may provide a reference for future research. [ABSTRACT FROM AUTHOR]

Background Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. Methods We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Results Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. Limitations First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Conclusions Our findings support the hypothesis that BDNF is involved in the pathophysiology of mental disorders, not only OCD but also GAD. OCD and GAD patients both show lower BDNF plasma levels compared to healthy controls. The BDNF plasma levels are not associated with Val66Met variation. [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]

The homo sapiens nuclear receptor subfamily 4, group A ( NR4A2 ) genetic variation has been implicated as a risk factor for schizophrenia (SZ). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-analysis to quantify the impact of NR4A2 variation on the risk of SZ. All eligible case-control studies published up to September 2014 were identified by searching PubMed OVID, EBSCO, PsycINFO and ISI web of knowledge. Pooled odds ratio with 95% confidence interval were used to access the strength of association in fixed- or random-effects model. Seven studies that reported 17 variants with a total of 3027 participants were included. Of these variants, five ones (rs143618355, rs199674295, c.366-369 del TAC, c.-469delG and P4) were present only in cases, and three ones (rs35479735, rs3832066 and rs397706674) were available for meta-analysis. Overall, there was no significant association between the three variants and SZ risk under allele model, dominant model and recessive model. The results failed to reveal significant link between NR4A2 polymorphism and SZ risk. However, large-sized and well-designed studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor A ( VEGFA ) has been implicated in neurotrophy and neurogenesis, which play a pivotal role in brain development and may be involved in the pathophysiology of schizophrenia (SCZ). We hypothesized that common genetic variants in the VEGFA gene may be associated with SCZ. In our study, seven tag single nucleotide polymorphisms (SNPs) within VEGFA were genotyped in 1034 SCZ patients and 952 healthy controls in the Han Chinese population. No significant differences of allele and genotype distributions of the 7 tag SNPs were identified between SCZ patients and healthy controls. The AA genotype of rs699947 nominally decreased the risk of SCZ in recessive inheritance model ( p = 0.03, OR = 0.65, 95%CI = 0.44–0.95, adjusted p = 0.18). No significant associations were found between different haplotypes and the risk of SCZ ( p > 0.05). Our findings suggested that the selected tag SNPs of VEGFA may not confer a susceptibility of SCZ in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Accumulating evidence has implied that serotonin system dysfunction may be involved in the etiology of anorexia nervosa (AN). Serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is the genetic variant coding for the serotonin transporter and has a modulatory effect on its expression. This study aimed to investigate the possible association between the 5-HTTLPR and the susceptibility and severity of AN in Han Chinese using a case-control (255 patients and 351 controls) and family based study (198 trios). Eating disorder examination was used to measure the severity of AN behavioral symptoms. For the case-control study, the 5-HTTLPR showed significant association with AN in our sample (genotypic P = 0.03). The frequency of S allele was significantly higher in patients than that in controls (OR = 1.38, 95%CI: 1.06–1.79, P = 0.017). For the family-based study, the S allele of 5-HTTLPR was preferentially transmitted rather than non-transmitted from the parents to affected offspring (P = 0.013). The results of ANCOVA test revealed no significant association between the 5-HTTLPR polymorphism and severity of AN. Our findings suggested that 5-HTTLPR is able to confer susceptibility to AN in Han Chinese. [ABSTRACT FROM AUTHOR]

Background Patients with schizophrenia using antipsychotics often develop metabolic side effects, especially with clozapine. Previous studies indicated that antipsychotics could activate the pathway of the sterol regulatory element-binding protein (SREBP). The sterol regulatory element binding transcription factor 2 ( SREBF2 ) gene mainly regulates the cholesterol biosynthetic gene. Therefore, we hypothesized that the SREBF2 gene would be a candidate gene for interindividual variation in drug-induced metabolic syndrome (MetS). In this genetic case–control study, we examined the SREBF2 gene polymorphisms in the risk of MetS patients treated with clozapine. Methods Ten single nucleotide polymorphisms (SNPs) of SREBF2 were genotyped in a CHB (Han Chinese in Beijing, China) population, a sample of 621 schizophrenia patients treated with clozapine. Patients were evaluated for metabolic parameters and screened for the MetS criteria. Results The incidence of MetS among all subjects was 41.8% (260/621). Two markers of SREBF2 were associated with MetS induced by clozapine after False Discovery Rate (FDR) correction (rs1052717, corrected P allele = 0.010, corrected P genotype = 0.022; and rs2267443, corrected P genotype = 0.015). Patients who received clozapine and carried the A-allele of rs2267443 or rs1052717 had an increased risk of MetS (rs2267443, odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.20–2.34; and rs1052717, OR = 1.81, 95% CI: 1.15–1.98), adjusted by logistic regression for clinical characteristics. Conclusion The results suggest that the genetic polymorphisms of SREBF2 gene may be associated with MetS in patients treated with clozapine. [ABSTRACT FROM AUTHOR]

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits and repetitive behaviors with restricted interests. A previous quantitative proteomic profiling study demonstrated that microtubule-associated stable tubule only polypeptide (STOP; also known as MAP6) protein was significant reduced in the cerebral cortex from BTBR mouse model of autism compared to the C57BL/6J mice. In the present study, the result showed that the concentration of STOP/MAP6 protein was significantly reduced in the plasma of autistic subjects than that in healthy controls. Finally, a possible mechanism of STOP/MAP6 protein in the pathogenesis of autism was proposed. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several lines of evidence have suggested that has-mir-206 (miRNA-206) may regulate brain-derived neurotrophic factor (BDNF) protein synthesis. The primary aim of this study was to determine whether miRNA-206 gene (MIR206) may confer susceptibility to bipolar disorder type I (BD-I) and treatment response to mood stabilizers. Also, we intended to verify the hypothesis that a potential interplay of MIR206 and BDNF may influence the genetic risk for BD-I and treatment response. Methods: The MIR206 rs16882131 and BDNF rs6265 polymorphisms were genotyped in 280 BD-I patients and 288 healthy controls. Treatment response to lithium and valproate was retrospectively determined. Results: No association was observed in the individual polymorphism with regards to risk of BD-I and treatment response. Our results showed a significant gene to gene interaction between the MIR206 rs16882131 and BDNF rs6265 polymorphisms that contribute to BD-I susceptibility and treatment response. Further analysis showed a significant interaction between MIR206 and BDNF on treatment score (F 3, 138=8.61, P=0.046), and individuals with MIR206 T/T+TC and BDNF A/A genotypes had a significantly lower mean treatment score than those with MIR206 CC and BDNF A/A+A/G as well as those with MIR206 CC and BDNF G/G genotypes (P=0.018 and 0.013, respectively). Limitation: This is a preliminary investigation with relatively small sample size. Conclusion: Our findings provide initial evidence of the gene-to-gene interaction of MIR206 and BDNF in regards to the risk for BD-I as well as treatment response to mood stabilizers. [Copyright &y& Elsevier]

Rationale: Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported. Objectives: This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment. Methods: A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol. Results: MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P = 0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients ( P = 0.009), but not among males ( P = 0.07). Conclusions: Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients. [ABSTRACT FROM AUTHOR]

Abstract: Neuropsychological endophenotype approach is an emerging strategy in schizophrenia research to understand and identify the functional importance of genetically transmitted, brain-based deficits present in this disorder. Accumulating evidence indicated that working memory deficit is a core neuropsychological dysfunction in schizophrenia and a primary endophenotype indexing the liability to develop schizophrenia. Genetic variation in ankyrin 3 gene (ANK3) is likely to have widespread cognitive effects. Our previous study has identified a significant association of ANK3 SNPs and schizophrenia. In this study, we aimed to examine whether the schizophrenia-risk SNPs within ANK3 may affect working memory deficits in schizophrenia patients. Herein, we assess the working memory performance in 163 patients with first-episode, antipsychotic-naïve schizophrenia and 42 sex, age-matched healthy subjects using N-back task. Two SNPs rs10761482 and rs10994336 were genotyped among the patients and 209 controls. Our results showed that schizophrenia patients showed significantly poorer performance than healthy controls on N-back task (ps<0.01). After adjusting for the scores of intelligence quotient, memory quotient and the demographic factors, there was a significant genotype effect of the rs10994336 on the accuracy rate and reaction time of 2-back item (p =0.048 and 0.024, respectively). Post-hoc analyses showed that patients with rs10994336T/T genotype had significantly lower accuracy rate and more reaction time at 2-back task than those with T/C and C/C genotypes. The association of SNP rs10994336 with schizophrenia was replicated in our sample (genotypic p =0.024 and allelic p =0.006). However, we did not find any significant association of rs10761482 with schizophrenia and parameters in N-back task. Our results indicated that genetic variation within ANK3 may exert gene-specific modulating effects on working memory deficits in schizophrenia. [Copyright &y& Elsevier]

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]

Introduction Estrogen plays essential roles in the regulation of food intake, adiposity, and body weight control. The estrogen alpha receptor, encoded by estrogen receptor 1 gene ( ESR1), has been implicated with anorexia nervosa ( AN). A previous study indicated that the rs2295193 polymorphism in ESR1 may confer a genetic susceptibility to AN. Methods In a case-control study, we assessed 195 AN probands and 93 healthy controls; 99 trios were studied in a family-based association analysis through genotyping the rs2295193 polymorphism in ESR1. Additionally, we carried out a meta-analysis of the combined sample groups. Results There were no significant differences in the genotype or allele frequencies of the rs2295193 polymorphism between the AN and control groups ( Ps > 0.05). In the transmission disequilibrium test ( TDT) analyses, there was no evidence for biased transmission of the G allele of rs2295193 polymorphism ( P = 0.32). In female-only samples, no significant association was observed between the rs2295193 polymorphism and AN in either case-control or transmission disequilibrium test analyses ( Ps > 0.05). The meta-analysis revealed that no excess of transmission of the G allele in AN families (pooled odds ratio = 1.10, P = 0.79). Discussion Meta-analytically combined evidence from the present genotyping and the literature showed that rs2295193 polymorphism in ESR1 is not a major genetic susceptibility factor in AN. [ABSTRACT FROM AUTHOR]

Rationale: Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive-compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology. Objectives: This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms. Methods: A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped. Results: Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene-gene interaction model ( p = 0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score ( F = 7.650, p < 0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT. Conclusions: These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine. [ABSTRACT FROM AUTHOR]

Previous researches showed that the dopamine receptor D1 (DRD1) may play a critical role in drug dependence. This research aimed to determine whether DRD1 played a role in development of heroin dependence in Chinese heroin-dependent patients. 465 Chinese Han heroin-dependent subjects and 379 healthy controls were recruited in the Shanghai region. Five single-nucleotide-polymorphisms (SNPs) of the DRD1 gene were genotyped in all subjects. The results found that the frequencies of DRD1 SNP genotypes or haplotypes were not different between heroin-dependent patients and controls. Among heroin-dependent patients, subjects with rs5326CC and/or rs6882300AA genotypes develop to heroin-dependent more rapidly than those without rs5326CC and/or rs6882300AA genotypes. The results indicated that DRD1 gene polymorphism may not play an important role in the susceptibility of heroin dependence in the Chinese Han population, but it may be associated with the rapidity of heroin dependence development from first drug use. [ABSTRACT FROM AUTHOR]

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]