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Linkage Disequilibrium Analysis and Functional Study of Schizophrenia-Related Genes

Author: TangRuZuo
Tutor: HeLin
School: Shanghai Jiaotong University
Course: Biochemistry and Molecular Biology
Keywords: Schizophrenia linkage disequilibrium case-control study transmission disequilibrium test functional study
CLC: R749.3
Type: PhD thesis
Year: 2008
Downloads: 512
Quote: 0
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Abstract


Schizophrenia is a severe psychiatric disorder that affects about 1% of the world’s population. The disorder is characterized by psychotic symptoms in particular delusions and hallucinations, reduced interest and drive, altered emotional reactivity and disorganised behaviour. It is suggested that schizophrenia is contributed by genetic and environmental factors, and genetic factors play a dominant role in the pathogenesis of the disorder. Nevertheless, unlike other simple Mendalian diaseases, schizophrenia is of a very complex inheritance model. There are multiple susceptibility genes, each of small or moderate effect, acting collaboratively with environmental factors. Moreover, schizophrenia is absent of a diagnostic neuropathology or other biomarkers. Therefore, the search for chromosome loci and genes have been slow and frustating.During the past two decades, linkage and association studies have been the main approaches in searching for complex disease genes. To date, there have been several successful examples where candidate genes such as NRG1, G72, DTNBP1 were identified through association analysis targeting chromosome regions first identified by linkage study. These achievements have fueled the hope that similar approaches will be effective in the search for other genes underlying predisposition to schizophrenia. Moreover, to confirm a candidate gene, unequivocal replications among different populations remain the top priority.Here, we report the study evaluating the relevance of Epsin 4 and schizophrenia. We genotyped 6 markers and performed transmission disequlibrium test in 308 Chinese trios. Although no individual marker was significant at the P<=0.05 level, the haplotypes detected in our samples showed strong evidence of association (most significant global P=0.002). Our results indicate the presence of a locus near the 5’end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.We also conducted a case control study of 2 SNPs within PIK3C3 promoter region in 556 unrelated schizophrenia patients and 563 normal controls and discovered obvious differences in allele frequency between patients and controls. In addition, luciferase reporter array system was used to evaluate the influence of haplotypes on gene transcription. Compared to HapC/-, HapT/C can significantly weaken promoter’s transcriptional activity (P=0.002, t-test). In summary, our results do support PIK3C3 play a significant role in the etiology of schizophrenia.Both case-control study and transmission disequilibrium test in Chinese samples suggest that IL10 is a schizophrenia susceptibility gene. Since the associated SNPs located in promoter region, we tried to detect if these SNPs would influence gene function. First, we carried out Electrophoretic Mobility Shift Assay (EMSA) to investigate the binding difference of SNPs and transcription factors. Then, luciferase reporter array system was conducted to test if haplotyes could affect gene transcription. However, both EMSA and luciferase reporter array system revealed no positive results. Therefore, we concluded that the SNPs in the promoter regions of IL-10 were just in linkage disequilibrium with another locus which exert more significant predisposition to schizophrenia.Combining linkage disequlibrium analysis and functional study, we investigated the relevance of Epsin 4、PIK3C3、IL10 and schizophrenia, and this would provide new clues for the genetic study of schizophrenia.

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CLC: > Medicine, health > Neurology and psychiatry > Psychiatry > Schizophrenia
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