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Genetics Study of Candidate Genes for Schizophrenia

Author: LiWenJun
Tutor: WeiJun;JuGuiZhi
School: Jilin University
Course: Medical Genomics
Keywords: Schizophrenia single nucleotide polymorphisms association analysis candidate gene PCYT1A PCYT1B NOTCH4 BDNF COMT
Type: PhD thesis
Year: 2008
Downloads: 368
Quote: 4
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Schizophrenia is a common and serious mental disorder, whose pathogenesis remains undefined. Family, twins, and adoptive studies have precisely indicated a genetic component may be involved in schizophrenia. Studies of schizophrenia on genome scanning and candidate gene have acquired many positive results, but most of these results produce poor replication. So far, the major and specific susceptibility genes leading to schizophrenia remains unidentified.ObjectiveTo investigate a genetic association between schizophrenia and polymorphisms of 5 genes, including PCYT1A、PCYT1B、BDNFNOTCH4 and COMT, 11 SNPs in these 5 genes were detected. The PCYT1A and PCYT1B genes encode CTP-phosphocholine cytidylyltransferase, which is the rate-limiting enzyme for the phosphatidylcholine biosynthetic pathway. BDNF, NOTCH4 and COMT are involved in the neural development. The present study tried to reveal the predisposing genes and molecular genetic mechanism of schizophrenia.MethodsThe study of the polymorphisms of possible genes for schizophrenia is carried out through the family-based analysis and the case-control study. The samples of parent-offspring trios consisting of fathers, mothers and affected offspring with schizophrenia, were recruited at two psychiatric hospitals based in Siping and Changchun respectively. In the case-control study, patients with schizophrenia were recruited in Beijing Huilongguan hospital and the control subjects were well matched in sex, age and ethinicity. All subjects are Chinese Han origin and all patients with schizophrenia were diagnosed using the ICD-10 and CCMD-II-R.All the subjects gave written informed consent for the genetic analysis and peripheral blood samples were then taken from them. Genomic DNA used for PCR amplification was extracted from the whole blood sample using a DNA extraction kit (Promega, USA). We genotyped 11 polymorphic SNPs using PCR-RFLP technology, including rs3772108 in the PCYT1A gene,rs17265665 and rs5986698 in the PCYT1B gene,rs6265, rs12273539, rs10835210 and rs2030324 in the BDNF gene,rs520688 and rs415929 in the NOTCH4 gene, rs740603 and rs4818 in the COMT gene. The 3 SNPs in the PCYT1A and PCYT1B genes were genotyped with family-trio samples and 8 SNPs in the other three genes were genotyped with case-control samples.The Hardy–Weinberg equilibrium for genotypic distributions was tested using the chi-square (χ2) goodness-of-fit test. The description of data, case-control analysis and association analysis between SNPs and psychiatric symptom, clinical subtype and premorbid personality were performed with the SPSS12.0 program. The haplotype-based haplotype relative risk test (HHRR) , transmission disequilibrium test (TDT), haplotype analysis and quantitative trait analysis were performed with the UNPHASED2.404 program.Results(1)Hardy-Weinberg equilibrium testThe chi-square (χ2) goodness-of-fit test showed that the genotypic distributions of these 9 SNPs were in Hardy-Weinberg equilibrium in the patient group (P>0.05), the parent group (P>0.05) and the control group (P > 0.05).(2)HHRR and TDT analysisThe HHRR analysis did not show disease association for rs3772108 in the PCYT1A gene (P>0.05), and rs17265665 and rs5986698 in the PCYT1B gen(eP > 0.05). The TDT also showed the same results.(3)Case-control analysisThe case-control analysis showed disease association for rs520688, rs4818 and rs2030324 in male patients, rs 6265 and rs 12273539 in female patients, and rs415929 in all patients(P<0.05). (4)Haplotype analysisThere was no haplotypic association for the rs17265665-rs5986698 haplotype system in the PCYT1B gene and the rs740603-rs4818 haplotype system in the COMT gene. However, the 1-df test showed preferential transmission for the rs520688(G)-rs415929(A) haplotype in the NOTCH4 gene, and for the rs12273539(T)-rs10835210(C), rs6265(A)-rs12273539(T)-rs10835210(C), rs12273539(T)- rs10835210(C)-rs2030324(C) and rs6265(G)-rs12273539(T)-rs10835210(C)-rs2030324(C) haplotypes in the BDNF gene. The rs12273539(C)-rs10835210(C)-rs2030324(C), rs6265(G)-rs12273539(C)-rs10835210(A)-rs2030324(C) and rs6265(A)-rs12273539(C)- rs10835210(C)-rs2030324(C) in the BDNF gene were excessively non-transmitted.In the female samples, there were 5 haplotypes showing preferential transmission, including the rs6265(G)-rs12273539(T)-rs10835210(A), rs6265(A)-rs12273539(C)- rs10835210(A), rs12273539(T)-rs10835210(C)-rs2030324(C), rs6265(G)-rs12273539(T)- rs10835210(C)-rs2030324(C) and rs6265(A)-rs12273539(C)-rs10835210(A)-rs2030324(C) haplotypes in the BDNF gene. Meanwhile, 9 individual haplotypes, including the rs6265(G)-rs12273539(T), rs12273539(T)-rs10835210(C), rs12273539(C)-rs10835210(C), rs6265(G)-rs12273539(T)-rs10835210(C), rs6265(A)-rs12273539(T)-rs10835210(C), rs6265(A)-rs12273539(C)-rs10835210(C), rs12273539(C)-rs10835210(C)-rs2030324(C), rs6265(G)-rs12273539(C)-rs10835210(C)-rs2030324(C) and rs6265(A)-rs12273539(C)- rs10835210(C)-rs2030324(C) haplotypes, showed disease resistance.In the male samples, there were no association between schizophrenia and all haplotypes as mentioned above.These findings suggested that the NOTCH4 and BDNF gene is likely to confer susceptibility to schizophrenia.(5)Associations between SNPs tested and positive symptomsThe SPSS for windows was applied to test for allelic and genotypic associations with positive symptoms. The result showed an association between delusion of influence and rs3772108. SNP rs17265665 showed an association with delusion of love and delusion of jealousy in both male and female samples, with incoherence of thinking in the male samples and with mind-reading, illogic thinking and delusion of jealousy in the female samples. SNP rs5986698 showed an association with delusion of influence in the male samples and with illogic thinking in the female samples. (6)Quantitative trait analysisThe quantitative trait analysis was performed using the UNPHASED program (version 2.404). SNP rs740603 was associated with many negative symptoms in patients with schizophrenia especially in female patients, such as blunted affect, emotional withdrawal, passive/apathy/social intercourse withdrawal and so on. SNPs rs4818, rs6265, rs12273539, rs10835210 and rs2030324 were associated with some positive symptoms, including incoherence of thinking, illusion, excitation and suspicion.(7)Association between SNPs tested and clinical subtypesBoth allelic and genotypic associations with clinical subtypes were tested using the SSPS program. SNPs rs5986698, rs12273539 and rs2030324 showed allelic association with clinical subtypes in female patients with schizophrenia.(8)Association between SNPs tested and premorbid personalityBoth allelic and genotypic associations with premorbid personality were tested using the SSPS program. The result showed that rs17265665 was associated with premorbid personality.ConclusionsAccording to the present results, it can be concluded that (1) the genetic polymorphisms of the NOTCH4, COMT and BDNF genes are likely to confer susceptibility to schizophrenia; (2) The effect of COMT genetic variation may be associated with negative symptoms in female patients with schizophrenia; (3) The effect of BDNF genetic variation may be associated with some positive symptoms and clinical subtypes in patients with schizophrenia; (4) No evidence shows association between the PCYT1A, PCYT1B genes and schizophrenia, but the two genes may be associated with some positive symptoms of schizophrenia.

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