Association Study Of NOS1AP And SNCA Gene Polymorphisms With Schizophrenia In A Chinese Han Population

Objective:1.Nitric oxide synthase 1 adaptor protein(NOS1AP)gene,encodes a receptor protein that can bind to and activate the neuronal nitric oxide synthase(NOS-I,encoded by NOS1)to produce nitric oxide(NO).Previous studies have confirmed that NO can interact with nNOS to produce specific accurate reaction to play a role under the mediated action of the structural region of NOS1AP,which participate in the pathogenesis of a variety of diseases such as Alzheimer's disease,Huntington's disease,cerebral ischemia,stroke and anxiety,and maintain normal physiological functions such as memory and learning.Evidence of the role of No in mental disorders has shown that the human NOS1 gene is also an symbol molecule of biological research.The interaction of NOS1AP and nNOS can be affected by the inhibitory function of nNOS,which is driven by the N-methyl-aspartate receptor complex--NMDA receptor,which plays a key role in neuronal function,and the dysfunction of NMDA receptor function can cause many obstacles.Some studies have confirmed that the development of neuronal dendritic spines and the absence of extensive cortical synaptic connections may be the initial pathogenesis of schizophrenia,which is an important neurological feature of schizophrenia.Excessive expression or deletion mutation of NOS1AP and interaction of NOS-I/NOS1AP can affect the normal growth and synaptic function of dendritic and spinous process,which leads to the abnormality of dopamine transmission,which may be related to schizophrenia.A large number of studies have shown that NOS1AP is a candidate gene for schizophrenia susceptibility.For the study of NOS1AP gene polymorphism and schizophrenia,there have been several studies in different area populations,which confirmed that NOS1AP gene polymorphism and schizophrenia,however the results were inconsistent.However,there was a lack of further research and analysis for the Chinese Han population.The purpose of our present study is to determine the association between four NOS1AP SNPs and schizophrenia in a large sample of Chinese Han population using the case-control method and PCR-RFLP(polymerase chain reaction-restriction fragment length polymorphism)to add new evidence for genetic research.2.The alpha-synapse protein gene(SNCA)encodes the alpha-synaptic nucleus(?-synuclein,?-syn),a member of the synaptic protein family,and a synaptic nucleus expressed mainly in neurons of the central nervous system.Previous studies suggested that the SNCA gene and its product?-syn were found and identified in the major pathological constituents of Parkinson's disease,Lewy body dementia,and multiple atrophy,so the SNCA gene and its products?-syn may play a role in the pathogenesis of neurodegenerative diseases.Some animal studies have confirmed that synaptic proteins in neurons have an important role in neuronal function and can adjust the homeostasis of dopamine,which may be associated with the onset of neurological diseases.In genetic studies,SNCA has a role in the survival of neurological diseases,mutations of SNCA gene can increase the expression of SNCA,which is associated with the risk of Parkinson's disease.According to the study of the corresponding diseases,the mutation of SNCA can influence the formation of nerve fibers,change the nerve fiber dynamics and morphology,and affect the function of dopaminergic neurons.Previously studies have been done about the correlation of SNCA in different populations,including the Chinese population,confirming the correlation between SNCA SNPs and Parkinson's disease.The specific role of?-syn itself in mental illness and schizophrenia is unknown,but studies have shown that mutations of SNCA may involve human development,including addiction and aggression,and that candidate genes related to addictive behaviour such as alcohol dependence include SNCA.In patients with alcohol dependence,they found variability in the carrying SNCA gene,the apparent increase in SNCA gene expression is closely related to the degree of alcohol dependence,possibly because the?-Syn encoded by the SNCA gene can regulate dopamine,which is an important neurotransmitter in alcohol addiction.SNCA may overlap in the pathogenesis of schizophrenia and Parkinson's disease,and the pathogenesis of schizophrenia is mainly related to dopamine-derived disorders,but early changes in DA originating from multiple risk factors and mutations in genetics are the core characteristics of schizophrenia.Because of the extensive research on SNCA and its effects on neuronal morphological structure and function and dopamine pathway,it is speculated that the SNCA gene may be associated with schizophrenia.But there is no research or report at home and abroad.The purpose of our present study is to determine the association between three SNCA SNPs(rs3822086C/T,rs11931074G/T,rs356219A/G)and schizophrenia in a Chinese Han population.Methods:1.Study subject:All schizophrenia participants recruited for the first part of this study were unrelated Chinese Han inpatients in Liaoning province.The schizophrenia group was made up of 218 males and 132 females,and have met the diagnostic criteria for schizophrenia.Healthy individuals without the presence of psychiatric disorders or serious physical illnesses in the same region of China were recruited as controls,consisting 249 males and 273 females.In the second part of this study,the schizophrenia group was made up of inpatients including 229 males and 131 females.Healthy control group was made up of healthy individuals,consisting 252 males and266 females.2.method:DNA purification,polymerase chain reaction(PCR)amplification and subsequent restriction fragment length polymorphism(RFLP)analysis were manipulated to determine genotypes.3.Statistically analysis:The Chi-square(X~2)test(or Fisher's exact test)and Odds ratios(ORs)calculation by version 22.0 of SPSS?software and Haploview version 4.2were used in our study.All the data was showed as frequency,or percentage,mean±SD.It was considered statistically significant when two-tailed P<0.05.Results:Association analysis of SNPs with schizophrenia:Part one:1.Between schizophrenia group and healthy group,the genotype and allele frequencies for rs1858232A/G differed significantly(?2=6.256,4.145;P=0.044,0.045),but neither genotype nor allele of rs4531275C/T differed significantly.The genotype frequencies and recessive models(TT/TC+CC)for rs4657178C/T differed significantly(?2=19.782,16.356;both P<0.01),and the genotype frequency for rs6704393C/T differed significantly(?2=12.683;P=0.002).2.In gender-specific association:Between SNPs and schizophrenia,there was no statistically significant difference in both male and female population for rs1858232A/G and rs4531275C/T.For rs4657178C/T,we found statistically significant difference in genotype and recessive models(TT/TC+CC)between male patients and controls(?2=9.356,7.987;P=0.009,0.006),and between female patients and controls(?2=9.585,7.159;P=0.008,0.011).For rs6704393C/T,there was a significant difference in the genotype frequency between male patients and controls(?2=8.800,P=0.012).3.In the haplotype analysis,only the TCT haplotype frequency differed significantly between the patients and controls in total population(?2=5.215,P=0.022).Part two:1.Between schizophrenia group and healthy group,neither genotype nor allele frequencies of rs3822086C/T,rs11931074G/T and rs356219A/G differed significantly.There was also no statistically significant difference in both male-and female-subgroup population.2.In the LDs and haplotype analysis,there was a strong LDs among rs3822086C/T,rs11931074G/T and rs356219A/G.The ATT and GTT haplotype frequency differed significantly between the patients and controls in total population(?~2=6.052,P=0.0139;?~2=4.508,P=0.0337).In gender specific analysis,the ATT haplotype frequency differed significantly between the patients and controls in female-subgroup population(?~2=4.219,P=0.04).No statistically significant difference of haplotypes was found in male-subgroup populationConclusions:1.G allele of rs1858232A/G,C allele of rs4657178C/T,and the TCT haplotype frequencies of rs6704393C/T,rs4531275C/T and rs4657178C/T may be risk factors for schizophrenia.2.The CC genotype of rs6704393C/T may be a protective factor for schizophrenia.3.These results provide novel evidence for an association between NOS1AP polymorphisms and schizophrenia in Han Chinese population,which is gender-specific.4.There was no association between SNCA polymorphisms and schizophrenia in Han Chinese population.5.The ATT haplotype may be a susceptible factor for schizophrenia.