Study Of The Association Between The Prostaglandin E Receptor 3 Gene Polymorphism And Schizophrenia

Schizophrenia is a group of undefined pathogenesis,high prevalence mental illness.Genetic studies have shown that schizophrenia is a multi-gene complex genetic disease.With the development of molecular biology technology,domestic and foreign scholars had done a great deal of research for schizophrenia susceptibility genes.At present there is no universally agreement for schizophrenia susceptibility genes although some positive results had acquired.Studies found that the concentration of prostaglandins occurred change in schizophrenia.Prostaglandins may play an important role in the pathogenesis of schizophrenia.ObjectiveTo investigate the association between the polymophism of prostaglandin E receptor 3 gene(PTGER3) and schizophrenia by detecting SNPs of PTGER3 with bioinformatics,epidemiology and molecular biology.This study attempted to reveal the susceptibility gene and molecular genetics mechanism of schizophrenia.MethodsA total of 240 Chinese parent-offspring trios of Han descent,consisting of fathers,mothers,and affected offspring with schizophrenia(165 males and 75 females),were recruited for the genetic analysis.These subjects originally came from Siping and Kaixuan psychiatric hospital during the period between 2000 and 2005. The patients were diagnosed as having a schizophrenic illness by using the International Classification of Diseases and Related Health Problems,Tenth Revision (ICD-10) and Chinese Classification and Diagnostic Criteria of Mental Disorders,the second revised edition(CCMD-2-R).The diagnosis was made independently by at least two psychiatrists.All the subjects had written informed consent for the genetic analysis and taken 5 mL blood from peripheral vein.Put the blood samples under -20℃deep-freeze until extracting genomic DNA.Using the DNA extraction kit(Promega,USA) to extract genomic DNA from the whole blood samples.We screened polymorphic SNPs by using PCR-RFLP analysis based on the SNP map of the genes for PTGER3 in the 240 parent-offspring trios,including rs12026099,rs2250312 and rs1022528.The Hardy-Weinberg equilibrium for genotypic distributions was tested using the chi-square(x~2)goodness-of-fit test.The haplotype relative risk test(HRR) and transmission disequilibrium test(TDT) were performed with the SPSS 13.0 program. The HRR and TDT were applied to test allelic association for a single locus.The haplotype analysis was performed with the UNPHASED program(Frank Dudbridge, MRC Biostatistics Unit Institute for Public Health,Cambridge,UK).The X~2 test was used to test the association between the SNPs of PTGER3 gene and clinical symptoms of schizophrenia.Results(1) The analytic results of the schizophrenia patients' basic informationThe results showed that in the 240 schizophrenia patients the range of age was from 14 years old to 48 years old,average age was 25.35±6.63 years old.Most schizophrenia(124) were at 20～29 years old.It was 51.7%of the whole patients. There was not significant difference(t=0.740,P=0.460) between the average age of sex.(2) Hardy-Weinberg equilibrium testThe Hardy-Weinberg equilibrium for genotypic distributions was tested using the chi-square(x~2)goodness-of-fit test.The goodness-of-fit test result showed that the genotypic distributions of the 3 SNPs were in Hardy-Weinberg equilibrium in both the patient group and the parent group(P＞0.05).(3) HRR analysisHRR analysis showed that the frequency distribution of PTGER3 gene SNPs locus rs12026099,rs2250312 and rs1022528 alleles were no significant difference (P＞0.05) between the transtmitted allele and untransmitted allele either in total samples or in clinical type grouping.This indicated no association between these 3 SNPs and schizophrenia.(4) TDT analysisTDT analysis showed that the probability of two different alleles of the PTGER3 gene SNPs locus rs12026099,rs2250312 and rs1022528 from heterozygous parents did not deviated from 50%(P＞0.05) either in total samples or in clinical type grouping.This indicated no association between these 3 SNPs and schizophrenia.(5) Haplotype analysisHaplotype analysis showed that rs2250312-rs1022528 locus was in the same LD block.The possibility of the haplotype formed of the two sites alleles transmitted to the next generation was more than the expected value of their free reorganization (D'=0.9233,r~2=0.8904).But the haplotype was not associated with schizophrenia (P＞0.05).(6) Association between the alleles,genotypes of SNPs and clinical symptomsIn the total samples,rs12026099 locus allele frequency distribution was associated with apathy(x~2=4.578,P=0.032).The other two SNPs locus were not associated with the clinical symptoms of schizophrenia(P＞0.05).In the paranoid type group,rs12026099 locus genotype frequency distribution was associated with illogic thought(x~2=6.100,P=0.047);rs2250312 locus allele frequency distribution was associated with illogic thought(x~2=4.471,P=0.034) and abulia(x~2=4.206,P=0.040);rs1022528 locus allele frequency distribution was associated with illogic thought(x~2=4.108,P=0.043)ConclusionAccording to the above-mentioned analytic results,we can reach the following conclusions:①rs12026099 locus was not associated with schizophrenia,but associated with apathy of schizophrenia and illogic thought of paranoid type schizophrenia;②rs2250312 locus was not associated with schizophrenia,but associated with illogic thought and poverty of thought of paranoid type schizophrenia;③rs1022528 locus was not associated with schizophrenia,but associated with poverty of thought of paranoid type schizophrenia;④the haplotype formed of rs2250312-rs1022528 locus was not associated with schizophrenia. To sum up,PTGER3 gene may not play a major role in schizophrenia development,but it was associated with some clinical symptoms of schizophrenia and clinical subtype of schizophrenia.Therefore,it may be as a minor gene in schizophrenia development.Its mechanism still needs further study.