Association Analysis Of Gene Polymorphisms On Synaptic Signal Transduction Pathway And Autism Spectrum Disorder

Objective:To explore the association among gene polymorphisms of synaptic signal transduction pathway and autism susceptibility in Chinese children,which could provide more understanding of the pathogenesis of autism and scientific theory evidence for intervention and treatment measures.Methods:A case-control study was performed to analysis 529 autistic children and1923 healthy controls.Ten genetic variants in six main genes(NLGN1,NRXN1,NRXN2,NRXN3,PSD95 and SHANK3)on the NRXN-NLGN-SHANK pathway that affect synaptic signaling were genotyped.We used goodness-of-fitχ~2 test to assess the Hardy–Weinberg equilibrium for genotypes.The differences in distribution of genotype and allele frequencies between cases and controls were calculated by Pearson’sχ~2 test.The unconditional logistic regression was performed to examine the association between genes on NRXN-NLGN-SHANK pathway and autism susceptibility.Gene-gene interactions were examined using logistic regression in additive and multiplicative model.The statistical analyses were carried out with SPSS13.0 and Stata11.0 software.Results:1.The study included 529 children with autism(mean ages 8.24±3.16 years)and 1923 healthy controls(mean ages 61.38±8.51 years).The sex proportion of control was matched with case,and the radio of male and female was 7:1.2.The results of unconditional logistic regression analysis showed that the mutation of NLGN1 rs9855544 A to G and NRXN3 rs12879016 T to G mutation significantly reduced the risk of ASD(OR=0.856,95%CI=0.746-0.981,P=0.025;OR=0.811,95%CI=0.699-0.941,P=0.006)and the mutation of NRXN2 rs12273892 A to T significantly increased the risk of ASD(OR=1.328,95%CI=1.133-1.557,P<0.001).To explore the influences of the three positive loci NLGN1 rs9855544,NRXN2rs12273892,NRXN3 rs12879016 between different genders,we used gender stratification analysis.We found that mutation in rs9855544 A to G and rs12879016 T to G in male also reduced the risk of ASD(OR=0.849,95%CI=0.732-0.985,P=0.030;OR=0.790,95%OR=1.677-0.930,P=0.005).Rs12273892 A to T mutation significantly increased the risk of ASD(OR=1.347,95%CI=1.134-1.600,P=0.001),but this effects were not found in female patients.3.Logistic regression model was used to evaluate the potential multiplicative and additive interactions among SNPs.We found that the interaction between rs9855544and rs12273892 was close to statistical significance(P=0.066).The multiplicative genotype model showed that comparing with individuals carrying rs9855544 GG genotype and rs12273892 AA genotype,individuals carrying rs9855544 AA+GA genotype and rs12273892 AA genotype increased the risk of ASD by 0.711 times(OR=1.711,95%CI=1.162-2.520).The ASD risk of individuals carrying rs9855544GG genotype and rs12273892 TT+AT genotype was increased by 1.507 times(OR=2.507,95%CI=1.553-4.047);the risk of ASD with rs9855544 AA+GA genotype and rs12273892 TT+AT genotype increased by 1.219 times(OR=2.219,95%CI=1.531-3.217).The interaction between other SNPs was not found.Conclusion:The genetic variation of NLGN1 rs9855544,NRXN2 rs12273892 and NRXN3 rs12879016 on the NRXN-NLGN-SHANK pathway affecting synaptic signal transduction was significantly correlated with the risk of autism and the effect on male was more obvious.NLGN1 rs9855544 and NRXN2 rs12273892 have probably significant multiplicative interactions,and individuals carrying the risk genotype of two SNPs will have a more pronounced effect on the risk of ASD.