Genetic Association Between The Polymorphism Of KPNA Family Genes And Schizophrenia

The human genome set is not only a stable but also a variable one. Thegenomic DNA is 99.9% identical to that of different persons and ethnics andalso 0.1% is variable. This stability in the structure makes the commonnessand constancies in the human species. During the long-term evolution,theuninterrupted mutations take place in the genome DNA arrays,and somesequence variants are maintained and they induced the differences andpolymorphisms in the different races and persons. About 90% variation of thehuman genome is attributed to single nucleotide polymorphisms (SNPs). Inrecent years,SNPs have been used as new DNA markers to replacemicrosatellites in mapping of disease-related genes in humans just becausethey are plentiful,stable and easy for assessment. A dense set of SNP markersopens up the possibility of studying the genetic basis of complex disease,suchas oncomas , cardiovascular and cerebrovascular diseases , neuro andpsychiosis,and it establishes the foundation of preventing,diagnosing andcuring diseases in gene's level.Schizophrenia is a serious mental disorder with a lifetime prevalence rateof 1% in the general population worldwide. It was characterized by theabnormal mental functions and disturbed behavior,which characteristicallyappear as a series of clinical features,such as positive and negativesymptoms,and disturbances in basic cognitive functions. The recurrence rateand mutilation rate of schizophrenia are very high,and the large sufferingpopulation has brought heavy economic burden to the society and families,threatening the safety and stability of society. Several lines of evidence fromepidemiological data suggest that genetic factors are likely to play an essentialrole in the developing of schizophrenia. Schizophrenia is not a simpleMendelian disease but looks like a complex disease involving several genes,with each susceptible gene having only a modest individual effect. Basically,there are two steps for mapping a disease-related gene in the human genome,the linkage-based genome-wide scan and the regional mapping with linkagedisequilibrium (LD) analysis. Genome-wide scanning shows that all thechromosomes except for chromosome 19, 21 and Y, may contain aschizophrenia susceptibility gene, while there are only 6 chromosomeregions whose positive regions could have a better reproducibility. Theyare1q21-22,5q22-23,6p24-21,8p22-21,13q14-33 and 22q11-12.This study was designed to search for a susceptible gene forschizophrenia by screening five SNPs on KPNA gene family. The study useda family-based analysis in which the family trios, consisting of father,mother and affected offspring were recruited. They were all Chinese Handecent in North China. Polymerase chain reaction and restriction fragmentlength polymorphism (PCR–RFLP)were adopted to examine individualgenotype. Statistical software SPSS was used to handle the data on genotype.Goodness of fit χ2 test was used to detect whether the SNPs distribution in thesample population is in Hardy-Weinberg equilibrium. Multifunctional geneticstatistical software were used to detect whether the tested SNPs locus wasassociated with schizophrenia by two family-based association analysis, thehaplotype relative risk (HRR) and the transmission disequilibrium test (TDT).Then we determined whether KPNA gene family was associated with.schizophrenia.Five SNPs were genotyped in this study, they were rs3762637(KPNA1),rs4470444(KPNA1), rs1451764(KPNA4), rs7357061(KPNA5) andrs6899918 (KPNA5). The goodness-of-fit test showed that the genotypefrequency distributions of these 5 SNPs were not deviated from theHardy-Weinberg equilibrium. Neither HRR nor TDT showed a geneticassociation between the 5 SNPs and schizophrenia. Schizophrenia has beencharacterized heterogeneously in clinical presentation. The clinicalheterogeneity may be related to genetic heterogeneity. To validate thishypothesis, we divided the patients into two groups based on the clinicalsymptoms. With the χ2 test, we can conclude that whether there were somesignificant differences of the frequencies distribution of allele and genotype intwo groups. And we can see this difference in the frequency distribution ofrs3762637 locus when we analyzed the negative symptom abulia (χ2=8.005,P=0.046). It is suggested that there was an association between rs3762637locus and one of the psychotic symptoms abulia. Also we can see thedifference in the frequency distribution of rs6899918 locus when we analyzedthe positive symptom bizarre behaviour(χ2=4.581,P=0.032). With the samereason, we can suggest that there was an association between rs6899918 locusand one of the psychotic symptoms bizarre behaviour.Besides, we detected 288 trios in the two SNP locus alias rs7357061 andrs6899918. As we all known, paranoid and undifferentiated patients accountfor the most part of the subgroups, so we analyzed the association between thetwo locus and the two kinds of schizophrenia. HRR showed associationbetween the two SNPs and paranoid patients(χ2 =6.096, P=0.014;χ2 =4.898,P=0.027). And TDT test also showed the association(χ2 =5.538, P=0.019;χ2=4.481, P=0.034). In the analysis between two SNPs and all the psychoticsymptoms of paranoid and undifferentiated patients, we can see many positiveresults. With them, we can confirm that the different heterogeneities in thedisease.The findings of this study suggested that KPNA gene family may notplay an important role in schizophrenia development. However,it may beassociated with some of the symptoms of schizophrenia. Therefore, itsmodest effect should not be excluded while the mechanisms need furtherstudy.