Association Between SHANK3 Polymorphisms And Susceptibility To Autism Spectrum Disorder

Autism spectrum disorder(ASD)is a kind of neurodevelopmental disorders and characterized by persistent lack of social communication and social interaction,as well as limited,repetitive and stereotyped behavior,interest or activity.Patients with ASD developed related symptoms when they are 12 to 18 months of age,and they are possible to be diagnosed by the age of two.The prevalence of ASD is increasing around the world.It was estimated by WHO in 2013 that the global prevalence of ASD is 1 in 160 children.ASD affects 4-5 times more males than females.Nowadays,there is no special treatment or drugs for ASD.ASD patients have poor outcomes,life-long disability and they need to be taken care of during their life.The etiology and pathogenesis of ASD is not clear now.Studies have shown that synaptic dysfunction in the brain may lead to ASD.Synaptic multi-domain skeleton protein encoded by SHANK3,plays an important role in the process of spinous process and synaptic plasticity.SHANK3 may be risk gene for ASD.However,results of studies on SHANK3 polymorphisms and ASD were inconsistent,and needs further study.Objective:Our study aimed to evaluate the association between single nucleotide polymorphisms(SNPs)of SHANK3 and ASD susceptibility.Methods:A total of 470 subjects were included in our case-control study,229 were cases from the second department of Pediatrics,the first hospital in Jilin University Bethune and the Spring Rehabilitation hospital in Jilin Province.241 were controls from the second department of Pediatrics,the first hospital in Jilin University Bethune.FiveSHANK3 SNPs(rs756638,rs4824116,rs76268556,rs9616915 and rs75767639)were genotyped by improved multiple ligase detection reaction(i MLDR).We used ?2 test to determine whether the genotype distribution were in Hardy-Weinberg equilibrium(HWE),and whether genotype and allele frequency distributions were significant different between the two groups.The linkage disequilibrium(LD)degree between the loci was calculated using Haploview4.2 software and the online SNPStats analysis program.The online SNPStats analysis program was used to analyze whether the five SNPs polymorphisms were associated with ASD under five different genetic models.Haplotype analysis was performed using the SNPStats online analysis program.Results:(1)A total of 229 ASD cases(191 males and 38 females)and 241 healthy controls(195 males and 46 females)were included in our study.The mean ages for cases and controls were both 4.00(3.00,5.00)years.No significant differences were found in gender and age distributions between the two groups(P>0.05).(2)All five SNPs genotype distributions were in HWE(P>0.05).(3)The mutant homozygotes genotypic frequencies of rs756638,rs4824116,rs76268556,rs9616915 and rs75767639 in cases were 5.7%,0.4%,0.0%,1.3%,and 0.4% respectively,and in controls were 2.9%,1.2%,1.2%,1.2% and 1.2% respectively.The mutant allelic frequencies in cases were 19.2%,9.4%,9.0%,10.3% and 8.8% respectively,and in controls were 16.7%,8.9%,7.5%,9.5% and 8.9% respectively.The genotypic and allelic frequencies of the five SHANK3 SNPs were not different between ASD patients and controls(P>0.05).(4)The optional inherited model of rs756638,rs4824116,rs76268556,rs75767639,were recessive model(ORGG vs CC/GC = 2.04,95%CI0.80-5.20,P = 0.13,AIC = 652.0),recessive model(ORTTvs CT/CC = 0.34,95%CI0.04-3.34,P = 0.32,AIC = 657.5),codominant model(ORTC vs CC = 1.52,95%CI0.91-2.54,P = 0.038,AIC=654.0),recessive model(ORGG vs CC/GC = 0.35,95%CI0.04-3.36,P=0.33,AIC=656.1).While for rs9616915,dominant model(ORCT/CCvs TT=1.09,95%CI 0.68-1.74,P=0.71,AIC=658.4),overdominant model(ORCTvs CC/TT=1.09,95%CI 0.68-1.77,P=0.71,AIC=658.4),and Log-additive model(OR=1.08,95%CI 0.71-1.64,P=0.74,AIC=658.4)were all the optional inherited model.(5)The frequencies of any haplotypes were not different between ASD patients and controls(P>0.05).Conclusion:(1)We found no association between rs756638,rs4824116,rs76268556,rs9616915 and rs75767639 polymorphisms and risk of Northern Chinese Han ASD.(2)We found no association between any haplotypes and Northern Chinese Han ASD.(3)SHANK3 may not be a susceptibility gene of Northern Chinese Han ASD.