| 1 | BMC Med. Genet. 2008 -1 9: 39 |
|---|---|
| PMID | 18460190 |
| Title | The estrogen hypothesis of schizophrenia implicates glucose metabolism: association study in three independent samples. |
| Abstract | schizophrenia is a highly heritable complex psychiatric disorder with an underlying pathophysiology that is still not well understood. Metaanalyses of schizophrenia linkage studies indicate numerous but rather large disease-associated genomic regions, whereas accumulating gene- and protein expression studies have indicated an equally large set of candidate genes that only partially overlap linkage genes. A thorough assessment, beyond the resolution of current GWA studies, of the disease risk conferred by the numerous schizophrenia candidate genes is a daunting and presently not feasible task. We undertook these challenges by using an established clinical paradigm, the estrogen hypothesis of schizophrenia, as the criterion to select candidates among the numerous genes experimentally implicated in schizophrenia. Bioinformatic tools were used to build and priorities the signaling networks implicated by the candidate genes resulting from the estrogen selection. We identified ten candidate genes using this approach that are all active in glucose metabolism and particularly in the glycolysis. Thus, we tested the hypothesis that variants of the glycolytic genes are associated with schizophrenia or at least with gender-associated aspects of the illness. We genotyped 185 SNPs in three independent case-control samples of Scandinavian origin (a total of 765 patients and 1274 control subjects). Variants of the mitogen-activated protein kinase 14 gene (MAPK14) and the phosphoenolpyruvate carboxykinase 1 (PCK1) and fructose-1,6-biphosphatase (FBP1) were nominal significantly associated with schizophrenia, and several haplotypes within enolase 2 gene (ENO2) consist of the same SNP allele having elevated risk of schizophrenia. Importantly, we find no evidence of stratification due to nationality or gender. Several gene variants in the Glycolysis were associated with schizophrenia in three independent samples. However, the findings are weak and not resistant to correction for multiple testing, which may indicate that they are either spurious or may relate to a particular subtype or aspect of the illness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Schizophr. Res. 2010 Jun 119: 219-27 |
| PMID | 20347265 |
| Title | MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. |
| Abstract | MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the stability and translation of mRNA targets. Increasing evidence suggests that miRNAs could be involved in the initiation and progression of neuropsychiatric disorders. Prior to this study, six miRNAs had been reported to show a significantly abnormal expression level in schizophrenic brains. Also, common single nucleotide polymorphisms within two miRNA transcripts have shown genetic associations with schizophrenia. However, it remains largely unknown whether variants in these miRNA genes and/or in their target sites are associated with schizophrenia. Here, we selected the above eight miRNAs, plus 15 of their experimentally validated target sites, as candidate susceptibility factors for schizophrenia, for mutation screening and further association studies in Chinese case-control samples. We identified a new potentially functional variant ss178077483 located in the pre-mir-30e, which was strongly associated with schizophrenia (allelic P=0.00017; genotypic P=0.00015), with an odds ratio of 4.952 (95% confidence interval: 1.887-12.998). We also demonstrated that this new variant ss178077483, combined with mir-30e rs7556088 and mir-24-MAPK14 rs3804452, showed a weak gene-gene interaction for schizophrenia risk (P=0.001). In addition, analysis of gene expression demonstrated that expression of the mature mir-30e in the peripheral leukocytes was significantly higher in patients' group than in the control group (P=6.79e-7).This is the first study to indicate that mir-30e ss178077483 plays a role in schizophrenia susceptibility. It suggests that the contribution of mir-30e to the processes that lead to schizophrenia should be further investigated. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Schizophr. Res. 2010 Jun 119: 219-27 |
| PMID | 20347265 |
| Title | MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. |
| Abstract | MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the stability and translation of mRNA targets. Increasing evidence suggests that miRNAs could be involved in the initiation and progression of neuropsychiatric disorders. Prior to this study, six miRNAs had been reported to show a significantly abnormal expression level in schizophrenic brains. Also, common single nucleotide polymorphisms within two miRNA transcripts have shown genetic associations with schizophrenia. However, it remains largely unknown whether variants in these miRNA genes and/or in their target sites are associated with schizophrenia. Here, we selected the above eight miRNAs, plus 15 of their experimentally validated target sites, as candidate susceptibility factors for schizophrenia, for mutation screening and further association studies in Chinese case-control samples. We identified a new potentially functional variant ss178077483 located in the pre-mir-30e, which was strongly associated with schizophrenia (allelic P=0.00017; genotypic P=0.00015), with an odds ratio of 4.952 (95% confidence interval: 1.887-12.998). We also demonstrated that this new variant ss178077483, combined with mir-30e rs7556088 and mir-24-MAPK14 rs3804452, showed a weak gene-gene interaction for schizophrenia risk (P=0.001). In addition, analysis of gene expression demonstrated that expression of the mature mir-30e in the peripheral leukocytes was significantly higher in patients' group than in the control group (P=6.79e-7).This is the first study to indicate that mir-30e ss178077483 plays a role in schizophrenia susceptibility. It suggests that the contribution of mir-30e to the processes that lead to schizophrenia should be further investigated. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Psychol Med 2013 Mar 43: 619-31 |
| PMID | 22850347 |
| Title | MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse. |
| Abstract | Adolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14-CNR1 gene-gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis. We genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA. Of the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype × marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype × marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse. Given that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14-CNR1 gene-gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | PLoS ONE 2015 -1 10: e0133404 |
| PMID | 26193471 |
| Title | Network-Based Analysis of Schizophrenia Genome-Wide Association Data to Detect the Joint Functional Association Signals. |
| Abstract | schizophrenia is a common psychiatric disorder with high heritability and complex genetic architecture. Genome-wide association studies (GWAS) have identified several significant loci associated with schizophrenia. However, the explained heritability is still low. Growing evidence has shown schizophrenia is attributable to multiple genes with moderate effects. In-depth mining and integration of GWAS data is urgently expected to uncover disease-related gene combination patterns. Network-based analysis is a promising strategy to better interpret GWAS to identify disease-related network modules. We performed a network-based analysis on three independent schizophrenia GWASs by using a refined analysis framework, which included a more accurate gene P-value calculation, dynamic network module searching algorithm and detailed functional analysis for the obtained modules genes. The result generated 79 modules including 238 genes, which form a highly connected subnetwork with more statistical significance than expected by chance. The result validated several reported disease genes, such as MAD1L1, MCC, SDCCAG8, VAT1L, MAPK14, MYH9 and FXYD6, and also obtained several novel candidate genes and gene-gene interactions. Pathway enrichment analysis of the module genes suggested they were enriched in several neural and immune system related pathways/GO terms, such as neurotrophin signaling pathway, synaptosome, regulation of protein ubiquitination, and antigen processing and presentation. Further crosstalk analysis revealed these pathways/GO terms were cooperated with each other, and identified several important genes, which might play vital roles to connect these functions. Our network-based analysis of schizophrenia GWASs will facilitate the understanding of genetic mechanisms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |