Screening Functional Alleles Of Susceptible Genes Of Schizophrenia

Schizophrenia is kind of serious psychiatric disease with the disease incidence being about 1% among common population. Most patients are incurable permanently. By meta-analysis and microRNA-based bioinformatics prediction software, we scooped some susceptible genes and some potentially functional SNPs. These SNPs can regulate the mRNA expression of some critical genes and thus play a very important role in schizophrenia. Our findings hold great significance for further experimental studies of the SNPs functions in schizophrenia.Theγ-amino butyric acid is synthesized by glutamate decarboxylase (GAD1) and is involved in a number of neural disorders. But the results of the the association between GAD1 and schizophrenia have been inconsistent. We therefore performed the meta-analysis to try to reconcile the inconsistency and to clarify the contribution of the GAD1 to schizophrenia. We collected all the published association studies up to August 2008 involving thirteen studies. The results showed no association for SNPs of GAD1 with schizophrenia and other psychic disorders. Interestingly, the risk attached to haplotypes in one block spanned the whole glutamate decarboxylase gene 1, and these haplotypes contributed to the risk of neural disorders, especially schizophrenia. This meta-analysis may be the first to focus systematically on the genetic association of GAD1 in neural disorders. It suggests the potential roles of the whole GAD1 genome, yet not a single locus in the pathogenesis of schizophrenia and other psychic disorders.NRG1 is another most researched gene with schizophrenia. However, studies of the association of NRG1 with schizophrenia have so far produced inconclusive and even conflicting results. We performed a meta-analysis of 26 published case-control and family-based association studies up to September 2008. 8049 cases, 8869 controls and 1515 families were analyzed. We found that: ( 1 ) Kazeem's or Lohmueller's Method makes no difference to synthesize family and case-control studies; ( 2 ) the association analysis of case-control studies was statistically consistent with family studies;( 3 )Part of the markers showed significant association with schizophrenia and the population heterogeneity was evident; (4)The 22 risk genes in the network were unconnected to each other, underlining the independent multi-etiologies involved in schizophrenia.miRNA is reported to be involved in neurological and psychiatric disorders, especially schizophrenia. In addition, robust association studies of schizophrenia have been carried out to identify positive mutations of allele. As polymorphisms in miRNA-binding sites (PolymiRTS) might affect the binding of miRNA to its targets, whether polymorphisms in miRNA-binding sites of the positive genes in schizophrenia hold functions remain undetermined. In this study, 425 genes associated with schizophrenia or located in linkage regions were selected to predict the putative miRNA-binding sites by means of specialized algorithms (pictar, microinspector, rnahybrid, miRbase, miRanda). Then, 803 SNPs within the putative binding sites were identified and their ability to affect or impair the binding with the miRNA was weighted by assessing theΔG and the variation ofΔG (ΔΔG, Gibbs free energy), through comparing the wild-type and variant alleles. In addition, the association of such 803 SNPs with schizophrenia and other diseases was searched in Szdabase and Pubmed and their potential putative functions were analyzed. The findings are as follows: (1) Part of the putative PolymiRTS were associated with schizophrenia in more than 3 studies, including rs10759 of RGS4 , rs165599 of OMT, and rs372055 of PRODH, etc; (2) Putative polymiRTS associated with other disease might be potential positive SNPs in schizophrenia. (3) Putative polymiRTS not reported before might be potential positive SNPs in schizophrenia. All together, the identified potentially functional polymiRTS in this study hold great significance for the design of future association studies as well as experimental miRNA-function studies in schizophrenia.All together, great improvements have been achieved in the methods of meta-analysis of GAD1 and NRG1 with psychiatric disorders. And the results suggested strongly that a single SNP doesn't contribute to the complex diseases significantly and the population heterogenetity are very important. Better hereditary methods are required urgently to manage such complex diseases. The PolymiRTS screening makes great significance for further case-control analysis for schizophreniagenetic research as well as for experimental research of SNPs functions in vitro or invivo.