Association Study On Polymorphisms And Gene-gene Interaction Of Wnt Signaling Pathway Related Genes With Autism In Chinese Han Population

BackgroundAutism is a neurodevelopmental disorder, Wnt signaling pathway is closely related to the nervous system development and synapse formation, and multiple genes in the pathway have been proved to associated with autism. Therefore, we hypothesized thae abnormal Wnt signaling pathway may play a role in the pathogenesis of autism.Objective1. To explore the association of Wnt signaling pathway related genes (Wnt2, APC, DISC1and En2gene) polymorphisms with autism in Chinese Han population.2. To explore the relationship between the gene-gene interaction of Wnt signaling pathway and autism in Chinese Han population.Methods1. Genome-wide SNP genotyping was peformed using Illumina HumanHap CNV370-Duo Chip in278autistic trios、157autistic individuals and97healthy controls, another338normal controls data came from genetic resource of central south university state key laboratory of medical genetics, Genotype data of76SNPs within Wnt signaling pathway related genes (Wnt2, APC, DISCI and En2gene) were selected. The association between these SNPs loci and autism were analyzed through single marker and haplotype case-control association analysis and family-based transmission disequilibrium test (TDT) by Haploview4.2software.2. Using Multifactor dimensionality reduction (MDR) to analyze gene-gene interaction of Wnt signaling pathway in autistic individuals. SNPs with Minor Allele Frequency (MAF) <5%and Hardy-Weinberg equilibrium P value<0.05, and individuals with missing SNP call rate>1%were removed from the analysis, a total of870subjects and65SNP locus were involved into the MDR test. The model with the highest cross validation, the highest testing accuracy as well as significant permutation test result would be selected as the best interaction model.Results1. Wnt2gene:(1) Case-control association analysis:6SNPs (rs887574, rs2896218, rs4727847, rs10487362, rs6947329and rs2239956) were involved for Case-control association analysis. There was not significant difference in the distribution of allelic and haplotypes frequency between autistic patients and controls(P>0.05).(2)5SNPs (rs2896218, rs4727847, rs10487362, rs6947329and rs2239956) were involved for TDT analysis. TDT showed no significant transmission disequilibrium in any alleles or haplotypes(P>0.05).2.APC gene:(1) Case-control association analysis:4SNPs (rs2431512, rs454886, rs2546110and rs411356) were involved for Case-control association analysis. There was not significant difference in and allelic frequency distribution between autistic patients and controls(P>0.05). The frequency distribution of AAGA haplotype constructed with rs2431512-rs454886-rs2546110-rs411356had a significant difference between the two groups (χ2=4.182, P=0.041).(2)4SNPs (rs2431512, rs454886, rs2546110and rs411356) were involved for TDT analysis. TDT showed no significant transmission disequilibrium in any alleles or haplotypes(P>0.05).3. DISCI gene:(1) Case-control association analysis:54SNPs were involved for Case-control association analysis.5SNPs (rs4658939, rs2793093, rs10495309, rs11122362, rs1073179) allelic frequency and4haplotypes (GGG and AAG constructed with rs4658939-rs2793093-rs10495309, GAA constructed with rs9432040-rs2356606-rs11122362and GG constructed with rs9431714-rs1073179) frequency had significant differences between autistic patients and controls (χ2value was4.704,4.915,5.568,4.043,5.183,5.315,4.467,4.043and5.183, respectively, and P value was0.030,0.027,0.018,0.044,0.023,0.021,0.035,0.044and0.023, respectively).(2)56SNPs were involved for TDT analysis. In the TDT analysis,2SNPs (rs4658945, rs11122362) and4haplotypes (AG constructed with rs10495310-rs4658945, GAA constructed with rs9432040-rs2356606-rs11122362, GA constructed with rs9431714-rs1073179, GAG constructed with rs821613-rs821639-rs16856189) showed significant transmission disequilibrium (χ2value was4.445,5.400,3.973,5.126,5.041,4.184, respectively, and P value was0.035,0.020,0.046,0.024,0.025and0.041, respectively).4. En2gene:(1) Case-control association analysis:1SNPs (rs1861958) was involved for Case-control association analysis. There was not significant difference in allelic frequency distribution between autistic patients and controls (P>0.05).(2)1SNPs (rsl861958) was involved forTDT analysis.TDT showed no significant transmission disequilibrium in rs1861958(P>0.05).5. MDR analysis showed that two loci combination constructed with rs2431512in APC gene and rs2793102in DISCI gene was the best interaction model of Wnt signaling pathway genes, which had the greatest CV consistency (4/10) and testing accuracy (0.4846).Conclusion1. The polymorphism of rs11122362and GAA haplotype constructed with rs9432040-rs2356606-rs11122362are associated with autism, DISCI gene is a susceptibility gene for autism in Chinese Han population. There was no significant association between Wnt2, APC and En2gene polymorphisms and autism in Chinese Han population.2. The interaction of APC gene and DISCI gene may participate in the pathogenesis of autism in Chinese Han population.