| 1 | Schizophr Bull 2011 Sep 37: 988-1000 |
|---|---|
| PMID | 20100784 |
| Title | Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. |
| Abstract | Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of HERV-W env-triggered BDNF. Our study provides new evidence for the involvement of HERV-W in the central nervous system, which will benefit the diagnosis and treatment of the devastating schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia |
| 2 | PLoS ONE 2013 -1 8: e74264 |
| PMID | 24069289 |
| Title | The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. |
| Abstract | The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| Title | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, NTRK2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. |
| SCZ Keywords | schizophrenia |
| 4 | Genetika 2015 Jul 51: 799-811 |
| PMID | 26410934 |
| Title | [The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars]. |
| Abstract | schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development. |
| SCZ Keywords | schizophrenia |
| 5 | Biol. Psychiatry 2015 Jan 77: 158-66 |
| PMID | 25034949 |
| Title | Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets. |
| Abstract | MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs. Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11.2 CNVs. We also performed a gene-set enrichment analysis of the predicted miRNA target genes. The schizophrenia group was enriched for the proportion of individuals with a rare CNV overlapping a miRNA (3.29-fold increase over comparison subjects, p < .0001). The presence of a rare CNV overlapping a miRNA remained a significant predictor of schizophrenia case status (p = .0072) in a multivariate logistic regression model correcting for total CNV size. In contrast, comparable analyses correcting for CNV size showed no enrichment of rare CNVs overlapping protein-coding genes. A gene-set enrichment analysis indicated that predicted target genes of recurrent CNV-overlapped miRNAs in schizophrenia may be functionally enriched for neurodevelopmental processes, including axonogenesis and neuron projection development. Predicted gene targets driving these results included CAPRIN1, NEDD4, NTRK2, PAK2, RHOA, and SYNGAP1. These data are the first to demonstrate a genome-wide role for CNVs overlapping miRNAs in the genetic risk for schizophrenia. The results provide support for an expanded multihit model of causation, with potential implications for miRNA-based therapeutics. |
| SCZ Keywords | schizophrenia |
| 6 | Pharmacogenet. Genomics 2015 May 25: 274-7 |
| PMID | 25751398 |
| Title | Hypothalamic-pituitary-adrenal system, neurotrophic factors and clozapine response: association with FKBP5 and NTRK2 genes. |
| Abstract | Clozapine is an atypical antipsychotic drug known as being more effective compared with traditional antipsychotics for patients with poor response or resistance to treatment. It has been demonstrated that clozapine modulates hypothalamic-pituitary-adrenal activity and affects central brain-derived neurotrophic factor levels, which could explain part of its therapeutic efficacy. In this study, we investigated the role of genes related to the hypothalamic-pituitary-adrenal axis (FKBP5 and NR3C1) and neurotrophic factors (BDNF and NTRK2) in clinical response to clozapine in 591 schizophrenia patients. We found significant allelic and genotype associations between FKBP5-rs1360780, NTRK2-rs1778929 and NTRK2-rs10465180 polymorphisms and clozapine response. The haplotypes composed of rs1360780-rs3777747-rs17542466-rs2766533 (FKBP5) and rs1619120-rs1778929-rs10465180 (NTRK2) were also nominally significant. Our results suggest that genetic variability in FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. Further studies are needed to clarify the involvement of these genes in clinical response to atypical antipsychotics. |
| SCZ Keywords | schizophrenia |
| 7 | Mol. Psychiatry 2015 Dec -1: -1 |
| PMID | 26666204 |
| Title | Polygenic associations of neurodevelopmental genes in suicide attempt. |
| Abstract | The risk for suicidal behavior (SB) is elevated in schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), but also occurs in subjects without psychiatric diagnoses. Genome-wide association studies (GWAS) on SB may help to understand this risk, but have been hampered by low power due to limited sample sizes, weakly ascertained SB or a reliance on single-nucleotide protein (SNP)-by-SNP analyses. Here, we tried to mitigate such issues with polygenic risk score (PRS) association tests combined with hypothesis-driven strategies using a family-based sample of 660 trios with a well-ascertained suicide attempt (SA) outcome in the offspring (Genetic Investigation of Suicide and SA, GISS). Two complementary sources of PRS information were used. First, a PRS that was discovered and validated in the GISS SA revealed the polygenic association of SNPs in 750 neurodevelopmental genes, which was driven by the SA phenotype, rather than the major psychiatric diagnoses. Second, a PRS based on three different genome-wide association studies (on SCZ, BPD or MDD) from the Psychiatric Genomics Consortium (PGC) showed an association of the PGC-SCZ PRS in the SA subjects with and without major psychiatric diagnoses. We characterized the PGC-SCZ overlap in the SA subjects without diagnoses. The extended major histocompatibility complex region did not contribute to the overlap, but we delineated the genic overlap to neurodevelopmental genes that partially overlapped with those identified by the GISS PRS. Among the 590 SA polygenes implicated here, there were several developmentally important functions (cell adhesion/migration, small GTPase and receptor tyrosine kinase signaling), and 16 of the SA polygenes have previously been studied in SB (BDNF, CDH10, CDH12, CDH13, CDH9, CREB1, DLK1, DLK2, EFEMP1, FOXN3, IL2, LSAMP, NCAM1, nerve growth factor (NGF), NTRK2 and TBC1D1). These novel genome-wide insights, supported by two lines of evidence, suggested the importance of a polygenic neurodevelopmental etiology in SB, even in the absence of major psychiatric diagnoses.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.187. |
| SCZ Keywords | schizophrenia |
| 8 | Transl Psychiatry 2016 -1 6: e758 |
| PMID | 26978740 |
| Title | A common NTRK2 variant is associated with emotional arousal and brain white-matter integrity in healthy young subjects. |
| Abstract | Dysregulation of emotional arousal is observed in many psychiatric diseases such as schizophrenia, mood and anxiety disorders. The neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) has been associated with these disorders. Here we investigated the relation between genetic variability of NTRK2 and emotional arousal in healthy young subjects in two independent samples (n1=1171; n2=707). In addition, diffusion tensor imaging (DTI) data in a subgroup of 342 participants were used to identify NTRK2-related white-matter structure differences. After correction for multiple testing, we identified a NTRK2 single nucleotide polymorphism associated with emotional arousal in both samples (n1: Pnominal=0.0003, Pcorrected=0.048; n2: Pnominal=0.0141, Pcorrected=0.036). DTI revealed significant, whole-brain corrected correlations between emotional arousal and brain white-matter mean diffusivity (MD), as well as significant, whole-brain corrected NTRK2 genotype-related differences in MD (PFWE<0.05). Our study demonstrates that genetic variability of NTRK2, a susceptibility gene for psychiatric disorders, is related to emotional arousal and-independently-to brain white-matter properties in healthy individuals. |
| SCZ Keywords | schizophrenia |