The Exploratory Study Of The Association Between Polymorphisms Of MTOR Pathway Genes And The Susceptibility,the Pharmacotherapy Effects In Schizophrenia

BackgroundsThe etiology of schizophrenia is elusive,and genetic factor is one of the major cuases.Previous researches suggested that mTOR(mammalian target of rapamycin)pathway played an important role during the development of central nervous system and the synaptic plasticity,it also took effects in the functional process of antipsychotics.Therefore,the current study explored the effect of mTOR pathway genes on the etiology and treatment of schizophrenia using genetic strategies.ObjectivesThe present study selected VEGFA,PTEN,TSC1 and TSC2 in the mTOR pathway as candidate genes to investigate whether the tag SNPs of the genes were individually and/or jointly contribute to schizophrenia.Meanwhile,we detected the mRNA expression levels of mTOR pathway genes PTEN,TSC1,TSC2,AKT1,mTOR and P70S6 K.Based on the prospective of gene polymorphisms and gene expression level,the present study aimed to explore the association between mTOR pathway genes and the susceptibility,the therapeutic effects of antipsychotics in schizophrenia.Methods 1.Tag SNPs of VEGFA,PTEN,TSC1 and TSC2 were selected and the samples were genotyped by Taqman probe and SNaPshot method in 1034 schizophrenia patients and 1339 healthy controls.The frequencies of alleles,genotypes,haplotypes and the gene-gene interaction were compared between the cases and controls to evaluate the risk of schizophrenia.2.The mRNA expression levels of PTEN,TSC1,TSC2,AKT1,mTOR and P70S6 K were detected by SYBR Green Real-Time PCR in the peripheral blood of 53 schizophrenia patients and 53 healthy controls.3.MassARRAY iPLEX Gold platform was used for genotyping the tag SNPs of PTEN,TSC1 and TSC2 in 268 schizophrenia patients.The efficacy and the side effect extrapyramidal symptoms were evaluated by Positive and negative symptom scale and Simpson-Angus Scale respectively.The association between the gene polymorphisms and the efficacy,the side effects EPS risk of antipsychotics were analysed.Results 1.Association study:(1)Among the selected 20 tag SNPs,3 SNPs(rs10434,rs2299941,rs12569998)were discarded for deviated from Hardy-Weinberg Equilibrium(HWE),2 SNPs(rs739441,rs1050700)were excluded for the low call rate,and the rest 15 SNPs(rs699947,rs25648,rs833070,rs3024997,rs3025030,rs3025035,rs532678,rs17562384,rs17107001,rs3761840,rs2809244,rs2074969,rs2074968,rs2072314,rs8063461)were included in the association analyses.(2)Single SNP analyses: The frequency of rs2074969(G>A)A allele was decreased in the case group(13.1% vs 16.0%),and the distribution of the genotypes was different between the case and control group.The frequency of rs8063461(G>A)A allele was higher in the case group(18.2% vs 15.4%),and there was difference for the distribution of the genotypes between the two groups.However,these differences didn’t survive the Bonferroni correction(P<0.05,adjusted P>0.05).The rest SNPs didn’t show allele,genotype nor haplotype association with schizophrenia risk(all P values>0.05).(3)Gene-gene interaction analyses: The best model of the analysis is a 3-loci model,rs8063461(TSC2)-rs2074969(TSC2)-rs532678(PTEN).The individuals who carry the high risk genotype of TSC2-PTEN had a 1.5246 fold higher risk for schizophrenia(OR=1.5246,95%CI=1.2846-1.8094).2.Gene expression analyses(1)The mRNA expression level of P70S6 K was decreased in the schizophrenia patients,but it didn’t survive the Bonferroni correction(P=0.027,adjusted P=0.162).The mRNA expression levels of the rest genes were similar between the schizophrenia patients and healthy controls(all P values>0.05).(2)Compared with GG genotype of rs2074969,the mRNA expression level of TSC2 was significantly decreased in the schizophrenia patients who were A allele carriers(P=0.004).3.Pharmacogenomics analyses(1)The whole sample: No significant association was detected between all the SNPs and theraputic efficacy,either the risk of EPS(all P values>0.05).The course of the disease was significantly associated with theraputic efficacy(B=-0.077,P=0.002),and disease course of the responders were shorter than the non-responders(6.77±7.38 years vs.11.43±10.63 years).The dosages of the antipsychotics that transformed to risperidone were asscociated with the risk of EPS(B=-0.329,P=0.023),and the dosage was lower in the EPS group(4.03±1.38 mg vs.4.55±1.53 mg).(2)Subgroup analyses(The sample treated with risperidone or paliperidone): There was no significant difference for the distribution of all of the SNPs between the responding and non-responding group(all P > 0.05).The patients with the genotype of best model rs12569998(PTEN)-rs3761840(TSC1)had a significantly higher possibility of effective treatment(P<0.0001,OR=3.9691,95%CI=1.9609-8.0339).The frequency of rs17107001(PTEN)-T carriers was significantly lower in the EPS group than the non-EPS group(P=0.041).Rs2074968(TSC2)-rs532678(PTEN)-rs3761840(TSC1)was the best model,and the risk of EPS was significantly increased in the patients with high risk genotypes(P<0.0001,OR=6.0786,95%CI=2.3998-15.3969).Conclusions 1.The present study didn’t figure out any tag SNP of VEGFA、PTEN、TSC1、TSC2 was significantly associated with schizophrenia susceptibility.The gene-gene interaction of TSC2 and PTEN could significantly increase the risk of schizophrenia.The mRNA expression level of TSC2 was significantly decreased in the schizophrenia patients who were rs2074969-A allele carriers.2.The interaction of PTEN-TSC1 was associated with the therapeutic efficacy of antipsychotics risperidone or paliperidone.The interaction of TSC1-PTEN-TSC2 were associated with EPS after resperidone or paliperidone treatment.