| Complex diseases also could be called common disease, which are influenced by the actions of multiple genes, their interactions with each other and also the environment. Some familiar complex diseases include schizophrenia, diabetic retinopathy, age-related macular degeneration, cardiovascular disease, et al. Since we know little about their pathogenesis, more and more scientists take part in research on the pathology and etiology of these complex diseases. The main work of my thesis is about linkage disequilibrium study on susceptible genes of schizophrenia and a diabetic retinopathy in Chinese population.Schizophrenia (MIM 181500) is one of the most serious mental illnesses which affect about 1% of the population worldwide. Data from twin, family, and adoption studies provide strong evidence that genetic factors play a very important role in schizophrenia. It is well known that schizophrenia is a kind of complex disease.The report comes from the Spain Basque district isolated population suggest that the polymorphisms in the promoter region of ADRA1A were associated with schizophrenia. ADRA1A located in 8p21, which was a hot candidate linkage region of schizophrenia. There are many other genes located in the region, such as DRP-2, PPP3CC, NRG1 and FZD-3, were reported to be associated with schizophrenia. We chose five polymorphisms, including the two positive SNPs, -563G/A and -9625G/A, and genotyped 960 case-control samples in our Han Chinese population by directly sequencing. No association was found in both genotyping and haplotype. It was thought that the promoter of ADRA1A is not a risk factor of schizophrenia.Evidences come from the study of postmortem brain of schizophrenia found that oligodendrocyte/myelination related genes were down-regulated compared with the healthy controls. OLIG2 is a transcription factor which could regulate the transcription of many oligodendrocyte/myelination related genes, and its expression level also was down-regulated in schizophrenia subjects. Therefore, OLIG2 is mostly like to be a risk gene of schizophrenia. We chose three polymorphisms and genotyped 617 case-control samples in our Han Chinese population by ligase detection reactions and directly sequencing to find out whether there is an association between the gene and schizophrenia. Our result indicates rs762178 was significantly associated with schizophrenia (p<0.05), and the haplotype A-T formed by rs762178 and rs1059004 was also significantly differed between schizophrenia and controls. Our result suggests that OLIG2 is a risk gene of schizophrenia in Chinese Han population, which also provided evidence for supporting the nerve development hypothesis of schizophrenia.QKI is a member of the RNA signal transcript and activation protein family, a gene located in 6q26–6q27. The main function of QKI is to regulate the differentiation and maturation of oligodendrocyte. Study from the postmortem brain of schizophrenia found that the expression level of QKI was significantly down-regulated. Then we supposed that QKI was a potential candidate gene of schizophrenia. We chose seven polymorphisms and genotyped 576 case-control samples in our Han Chinese population by directly sequencing to investigate the association between the gene and schizophrenia. No association was found in both genotyping and haplotype. The result suggested that QKI may not be a risk factor of schizophrenia.Diabetic retinopathy (DR) is a syndrome of diabetes, which could seriously influence the human healthy and life quality. The pathogenesis and development of DR are influenced by many conditions, such as the duration of diabetes, the control of blood sugar, as well as the genetic factors. Polymorphisms of many genes caused the individual difference of the disease.TNF-αis a multiple functional pro-inflammatory factor, which plays an important role in pathogenesis mechanism of diabetic retinopathy. The expression level of TNF-αwas found to be increased in the serum of DR patients and is positive related to the extent of the disease. We selected the TNF-αas our research object, chose three SNPs around its promoter and genotyped 288 case-control samples in our Han Chinese population by directly sequencing. No positive information was found between TNF-αand diabetics retinopathy. The result indicated that the promoter of TNF-αis not a risk region of DR in the Chinese Han population.The attachment section was about the research and development of AMLR (Allelic-specific Multiplexed Ligase-detection Reaction), a new genotyping technology. The technology is mainly based on the multiplex-PCR to amplify several polymorphisms synchronously. The PCR product is used as template for the ligation of special primer probe with the help of ligase. Then the genotypes of different SNPs could be easily distinguished by the different length of the ligased product. We think that AMLR would have a great prospect in the future genotyping field.
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