Research On Genetic Susceptibility,Prenatal And Perinatal Factors,and Gene-environment Interaction To Autism Spectrum Disorder

Objective:We aimed to explore the association of gene polymorphisms screened by GWAS strategy as well as prenatal and perinatal factors with autism susceptibility in Chinese children.Methods:We recruited 602 autistic children from 2 Maternal and Child Health Hospitals,4 Special Children’s Education Agencies and Wuhan Mental Health Center,as well as 604 healthy children from 8 primary schools and Luohu District Maternal and Child Health Hospital in Shenzhen.We screened GWAS SNPs based on expression quantitative trait loci(e QTL)analyses and bioinformatics databases.Eleven SNPs(LOC101928743 rs9467711,ITIH3 rs2535629,ITIH3 rs3617,AS3MT rs11191454,ZKSCAN3 rs6921919,MDK rs35324223,DGKI rs3735025,FES/FURIN rs4702,GALNT10 rs2434529,NT5C2 rs11191580,SFTA2 rs3095153)were genotyped in autistic children and healthy controls.Questionnaires about prenatal and perinatal factors were completed by parents or guardians.Univariate unconditional logistic regression was used to analyze the association between prenatal and perinatal factors and autism susceptibility.Goodness-of-fitχ~2test was used to assess the Hardy-Weinberg equilibrium for genotypes.The association between SNPs and autism susceptibility was analyzed by univariate unconditional logistic regression.Gene-gene interactions and gene-environment interactions were examined by constructing logistic regression model.The above analyses were conducted by SPSS14.0 and R3.6.1.Results:(1)Mean(SD)age of children with autism was 6.24(1.93),and that of healthy control was 5.39(2.43).The radio of male and female in both the cases and controls was 6:1.(2)The risk of autism was significantly associated with maternal infectious diseases(OR=4.235,95%CI=2.784-6.443),anemia(OR=1.954,95%CI=1.092-3.497),hypertension or diabetes(OR=2.539,95%CI=1.111-5.800),preterm birth(OR=1.979,95%CI=1.233-3.176),and cesarean section(OR=1.531,95%CI=1.206-1.945).(3)The risk of autism in children with ITIH3 rs2535629 GA genotype was higher than that in children with AA genotype(OR=1.511,95%CI=1.059-2.154).After gender stratification,we found that AS3MT rs11191454 A to G mutation reduced the risk of autism(OR=0.810,95%CI=0.670-0.980),and children with NT5C2 rs11191580 CT+CC genotype had higher risk of autism than children with TT genotype(OR=0.770,95%CI=0.610-0.990)in male sample.In the female sample,ITIH3 rs3617 CC genotype was associated with an increased risk of autism compared with the AA genotype(OR=2.583,95%CI=1.107-6.557).After correction by FDR multiple test,the above associations were non-significant.(4)Logistic regression model analysis showed that gene-gene interactions and gene-environment interactions were non-significant.Conclusion:Maternal infectious diseases,anemia,hypertension or diabetes,premature birth and cesarean section may increase the risk of autism.ITIH3 rs2535629,AS3MT rs11191454,NT5C2 rs11191580 and ITIH3 rs3617 may be the genetic susceptibility loci of autism among children in China.