Association analysis of genetic variant of rs13331 in PSD95 gene with autism spectrum disorders: A case-control study in a Chinese population

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by high heritability. Recently, autism, the most profound form of ASD, has been increasingly attributed to synaptic abnormalities. Postsynaptic density 95 (PSD95), encoding PSD protein-95, was found essential for synaptic formation, maturation and plasticity at a PSD of excitatory synapse. It is possibly a crucial candidate gene for the pathogenesis of ASD. To identify the relationship between the rs13331 of PSD95 gene and ASD, we performed a case-control study in 212 patients and 636 controls in a Chinese population by using a polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP) assay. The results showed that in genetic analysis of the heterozygous model, an association between the T allele of the rs13331 and ASD was found in the dominant model (OR=1.709, 95% CI 1.227–2.382, P=0.002) and the additive model (OR=1.409, 95% CI=1.104–1.800, P=0.006). Our data indicate that the genetic mutation C>T at the rs13331 in the PSD95 gene is strikingly associated with an increased risk of ASD.

Keywords

polymorphism / rs13331 / PSD95 / autism spectrum disorder

References

[1] SandinS, LichtensteinP, Kuja-HalkolaR, et al. . The familial risk of autism. JAMA, 2014, 311(17): 1770-1777 PMID: 24794370 PMCID: 4381277

[2] ElsabbaghM, DivanG, KohYJ, et al. . Global prevalence of autism and other pervasive developmental disorders. Autism Res, 2012, 5(3): 160-179 PMID: 22495912 PMCID: 3763210

[3] RumseyJM, RapoportJL, SceeryWR. Autistic children as adults: psychiatric, social, and behavioral outcomes. J AmAcad Child Psychiatry, 1985, 24(4): 465-473

[4] KaoYC, KramerJM, LiljenquistK, et al. . Association between impairment, function, and daily life task management in children and adolescents with autism. Dev Med Child Neurol, 2015, 57(1): 68-74 PMID: 25312547 PMCID: 4298704

[5] VisserEM, BergerHJ, Van SchrojensteinLVH, et al. . Cognitive shifting and externalising problem behaviour in intellectual disability and autism spectrum disorder. J Intellect Disabil Res, 2015, 59(8): 755-766 PMID: 25559338

[6] Baron-CohenS. Social and pragmatic deficits in autism: cognitive or affective. J Autism Dev Disord, 1988, 18(3): 379-402 PMID: 3049519

[7] EicherJD, GruenJR. Language impairment and dyslexia genes influence language skills in children with autism spectrum disorders. Autism Res, 2014, 8(2): 229-234 PMID: 25448322 PMCID: 4412753

[8] HeltM, KelleyE, KinsbourneM, et al. . Can children with autism recover? If so, how. Neuropsychol Rev, 2008, 18(4): 339-366 PMID: 19009353

[9] CohenS, ConduitR, LockleySW, et al. . The relationship between sleep and behavior in autism spectrum disorder (ASD): a review. J Neurodev Disord, 2014, 6(1): 44 PMID: 25530819 PMCID: 4271434

[10] GanzML. The lifetime distribution of the incremental societal costs of autism. Arch Pediatr Adolesc Med, 2007, 161(4): 343-349 PMID: 17404130

[11] AhmedaniBK, HockRM. Health care access and treatment for children with co-morbid autism and psychiatric conditions. Soc Psychiatry Psychiatr Epidemiol, 2012, 47(11): 1807-1814 PMID: 22322982

[12] MontesG HJ. Child care problems and employment among families with preschool-aged children with autism in the United States. Pediatrics, 2008, 122(1): 202-208

[13] NordenbaekC, JorgensenM, KyvikKO, et al. . A Danish population-based twin study on autism spectrum disorders. Eur Child Adolesc Psychiatry, 2014, 23(1): 35-43 PMID: 23661220

[14] FolsteinS, RutterM. Genetic influences and infantile autism. Nature, 1977, 265(5596): 726-728 PMID: 558516

[15] RosenbergRE, LawJK, YenokyanG, et al. . Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch PediatrAdolesc Med, 2009, 163(10): 907-914

[16] LichtensteinP, CarlstromE, RastamM, et al. . The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry, 2010, 167(11): 1357-1363 PMID: 20686188

[17] HallmayerJ, ClevelandS, TorresA, et al. . Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry, 2011, 68(11): 1095-1102 PMID: 21727249 PMCID: 4440679

[18] ZoghbiHY. Postnatal neurodevelopmental disorders: meeting at the synapse. Science, 2003, 302(5646): 826-830 PMID: 14593168

[19] van SpronsenM, HoogenraadCC. Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep, 2010, 10(3): 207-214 PMID: 20425036 PMCID: 2857788

[20] GaiX, XieHM, PerinJC, et al. . Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry, 2012, 17(4): 402-411 PMID: 21358714 PMCID: 3314176

[21] GylysKH, FeinJA, YangF, et al. . Synaptic changes in Alzheimer’s disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol, 2004, 165(5): 1809-1817 PMID: 15509549 PMCID: 1618663

[22] AartsM, LiuY, LiuL, et al. . Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science, 2002, 298(5594): 846-850 PMID: 12399596

[23] ChengMC, LuCL, LuuSU, et al. . Genetic and functional analysis of the DLG4 gene encoding the post-synaptic density protein 95 in schizophrenia. PLoS One, 2010, 5(12): e15107 PMID: 21151988 PMCID: 2996301

[24] ChenJ, YuS, FuY, et al. . Synaptic proteins and receptors defects in autism spectrum disorders. Front Cell Neurosci, 2014, 8: 276 PMID: 25309321 PMCID: 4161164

[25] TaftCE, TurrigianoGG. PSD-95 promotes the stabilization of young synaptic contacts. Philos Trans R SocLond B BiolSci, 2014, 369(1633): 20130134

[26] MigaudM, CharlesworthP, DempsterM, et al. . Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature, 1998, 396(6710): 433-439 PMID: 9853749

[27] LeubaG, WalzerC, VernayA, et al. . Postsynaptic density protein PSD-95 expression in Alzheimer’s disease and okadaic acid induced neuritic retraction. Neurobiol Dis, 2008, 30(3): 408-419 PMID: 18424056

[28] ChiocchettiAG, KoppM, WaltesR, et al. . Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach. Mol Psychiatry, 2014, 20(7): 839-849 PMID: 25224256

[29] ArkingDE, CutlerDJ, BruneCW, et al. . A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet, 2008, 82(1): 160-164 PMID: 18179894 PMCID: 2253968

[30] ShaoS, XuS, YangJ, et al. . A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chinese population. MolBiol Rep, 2014, 41(3): 1591-1595

[31] ChangSC, PaulsDL, LangeC, et al. . Sex-specific association of a common variant of the XG gene with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet, 2013, 162B(7): 742-750 PMID: 24132906

[32] LordC, CookEH, LeventhalBL, et al. . Autism spectrum disorders. Neuron, 2000, 28(2): 355-363 PMID: 11144346

[33] KennedyMB. Signal-processing machines at the postsynaptic density. Science, 2000, 290(5492): 750-754 PMID: 11052931

[34] Stephenson FA. Structure and trafficking of NMDA and GABAA receptors. BiochemSoc Trans, 2006,34(Pt 5):877–881

[35] UchinoS, WadaH, HondaS, et al. . Direct interaction of post-synaptic density-95/Dlg/ZO-1 domaincontainingsynaptic molecule Shank3 with GluR1alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor. J Neurochem, 2006, 97(4): 1203-1214 PMID: 16606358

[36] ZhengS, GrayEE, ChawlaG, et al. . PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. Nat Neurosci, 2012, 15(3): 381-388 PMID: 22246437 PMCID: 3288398

[37] ChenL, ChetkovichDM, PetraliaRS, et al. . Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature, 2000, 408(6815): 936-943 PMID: 11140673

[38] StathakisDG, HooverKB, YouZ, et al. . Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues. Genomics, 1997, 44(1): 71-82 PMID: 9286702

[39] HeZ, ShaoS, ZhouJ, et al. . Does long time spending on the electronic devices affect the reading abilities? A cross-sectional study among Chinese school-aged children. Res Dev Disabil, 2014, 35(12): 3645-3654 PMID: 25247847

[40] SunZ, ZouL, ZhangJ, et al. . Prevalence and associated risk factors of dyslexic children in a middle-sized city of China: a cross-sectional study. PLoS One, 2013, 8(2): e56688 PMID: 23457604 PMCID: 3574109

[41] FeyderM, KarlssonRM, MathurP, et al. . Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams’ syndrome. Am J Psychiatry, 2010, 167(12): 1508-1517 PMID: 20952458 PMCID: 3146008