TSC1、TSC2基因多态性和儿童孤独症的家系研究

中国儿童保健杂志 ›› 2013, Vol. 21 ›› Issue (6): 571-574.

TSC1、TSC2基因多态性和儿童孤独症的家系研究

刘漪,张燕霞,禹顺英,杜亚松

上海交通大学医学院附属精神卫生中心,上海 200030

收稿日期:2013-01-21 发布日期:2013-06-06 出版日期:2013-06-06
通讯作者: 杜亚松,E-mail:yasongdu@yahoo.com.cn
作者简介:刘漪(1972-),女,副主任医师,在职硕士,研究方向为儿童青少年精神病与精神卫生。
基金资助:
国家重点基础研究发展计划(973)(2010CB529602);上海市科委重点项目(11411952401);上海市新三年计划项目(GWIII-32)

Family-based association study of the TSC1,TSC2 genes polymorphisms in children with autism.

LIU Yi,ZHANG Yan-xia,YU Shun-ying,DU Ya-song.

Shanghai Mental Health Center,Shanghai Jiaotong University School of Medicine,Shanghai 200030,China

Received:2013-01-21 Online:2013-06-06 Published:2013-06-06

摘要/Abstract

摘要： 目的探讨结节性硬化症(tuberous sclerosis complex,TSC)相关基因TSC1、TSC2基因多态性与儿童孤独症之间的关联。方法利用SNaPshot基因分型技术,在97例孤独症核心家系中,对TSC1、TSC2基因上的8个标签SNP,即rs3761840、rs2809244、rs1050700、rs739441、rs2074968、rs2074969、rs2072314、rs8063461进行分型;通过FBAT软件及Haploview软件进行基于家系的单倍型分析。结果 1)基于家系的关联分析发现8个SNPs等位基因中有2个SNPs的等位基因倾向于过传递(rs1050700 A:Z=2.708,P=0.006769;rs2074968 G:Z=3.244,P=0.001180),并且经过FDR校正后,2个SNPs仍显示出与孤独症之间存在显著关联性(校正P值分别为0.027,0.014)。2)rs3761840-rs2809244基因型的单体型A-C显示出显著的传递不平衡,双亲较少传递给子女(Z=-2.297,P=0.021629)。rs2074968-rs2072314基因型的2种单体型即 G-C及C-C均显示出显著的传递不平衡,单体型G-C能从双亲过传递给子女(Z=2.596,P=0.009444),单体型C-C则相反(Z=-3.657,P=0.000256)。结论 TSC1、TSC2基因可能与儿童孤独症的发生存在关联。

关键词: 孤独症, TSC1, TSC2, DNA测序

Abstract: Objective To explore the characteristics of TSC1 and TSC2 genes polymorphisms in children with autism. Methods Eight tag single nucleotide polymorphisms (SNPs) were genotyped inTSC1 and TSC2 genes,from 97 autistic trios using SNaPshot technique.Single SNP haplotype association analysis were performed using the family-based association test (FBAT) and Haploview software. Resluts 1)In a family-based association test,two SNPs showed significant associations with autism (rs1050700 A:Z=2.708,P=0.006769;rs2074968 G:Z=3.244,P=0.001180).After the FDR correction,they all remained significant.2) Haplotype association analysis showed that three haplotypes,G-C(rs2074968-rs2072314),A-C( rs3761840-rs2809244),C-C(rs2074968-rs2072314)displayed the significant associations with autism. Conclusions The SNPs of TSC1 and TSC2 genes might be the susceptive genes in autism.It suggested that these genes polymorphisms might play the important roles in the pathogenesis of autism.

Key words: autism, TSC1, TSC2, DNA sequencing

中图分类号:

R749.94

刘漪,张燕霞,禹顺英,杜亚松. TSC1、TSC2基因多态性和儿童孤独症的家系研究[J]. 中国儿童保健杂志, 2013, 21(6): 571-574.

LIU Yi,ZHANG Yan-xia,YU Shun-ying,DU Ya-song.. Family-based association study of the TSC1,TSC2 genes polymorphisms in children with autism.[J]. journal1, 2013, 21(6): 571-574.

参考文献

[1] Ratajczak HV.Theoretical aspects of autism:causes-a review[J].J Immunotoxicol,2011,8(1):68-79.
[2] Ijichi S,Ijichi N.The prenatal autistic imprinting hypothesis:developmental maladaptation to the environmental changes between womb and the social world[J].Med Hypotheses,2004,62(2):188-194.
[3] Kelleher RJ,Bear MF.The autistic neuron:troubled translation[J].Cell,2008,135(3):401-406.
[4] Walsh CA,Morrow EM,Rubenstein JL.Autism and brain development[J].Cell,2008,135(3):396-400.
[5] Rutter M.Genetic studies of autism:from the 1970s into the millennium[J].J Abnorm Child Psychol,2000,28(1):3-14.
[6] Monaco AP,Bailey AJ.Autism:the search for susceptibility genes[J].Lancet,2001,S3:358-365.
[7] Geschwind DH.Genetics of autism spectrum disorders[J].Trends Cogn Sci,2011,15:409-416.
[8] Lee TL,Raygada MJ,Rennert OM.Integrative gene network analysis provides novel regulatory relationships,genetic contributions and susceptible targets in autism spectrum disorders[J].Gene,2012,496(2):88-96.
[9] Ratajczak HV.Theoretical aspects of autism:causes-a review[J].J Immunotoxicol,2011,8(1):68-79.
[10] Han S,Witt RM,Santos TM,et al.Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling[J].Cell Signal,2008,20(6):1084-1091.
[11] Matson JL,Hattier MA,Williams LW.How does relaxing the algorithm for autism affect DSM-V prevalence rates[J].J Autism Dev Disord,2012,42(8):1549-1556.
[12] Barrett JC,Fry B,Maller J,et al.Haploview:analysis and visualization of LD and haplotype maps[J].Bioinformatics,2005,21(2):263-265.
[13] Jeste SS,Sahin M,Bolton P,et al.Characterization of autism in young children with tuberous sclerosis complex[J].J Child Neurol,2008,23(5):520-525.
[14] Kopp CM,Muzykewicz DA,Staley BA,et al.Behavior problems in children with tuberous sclerosis complex and parental stress[J].Epilepsy Behav,2008,13(3):505-510.
[15] Curatolo P,Porfirio MC,Manzi B,et al.Autism in tuberous sclerosis[J].Eur J Paediatr Neurol,2004,8:327-332.
[16] Wiznitzer M.Autism and tuberous sclerosis[J].J Child Neurol,2004,19(9):675-679.
[17] de Vries PJ,Hunt A,Bolton PF.The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC):a postal survey of UK families[J].Eur Child Adolesc Psychiatry,2007,16(1):16-24.
[18] Sahin M.Targeted treatment trials for tuberous sclerosis and autism:no longer a dream[J].Curr Opin Neurobiol,2012,22(5):895-901.
[19] Kelleher RJ,Geigenmuller U,Hovhannisyan H,et al.High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism[J].PLoS One,2012,7(4):e35003.
[20] Schaaf CP,Sabo A,Sakai Y,et al.Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders[J].Hum Mol Genet,2011,20(17):3366-3375.
[21] Malisza KL,Clancy C,Shiloff D,et al.Functional magnetic resonance imaging of facial information processing in children with autistic disorder,attention deficit hyperactivity disorder and typically developing controls[J].Int J Adolesc Med Health,2011,23(3):269-277.
[22] Young DM,Schenk AK,Yang SB,et al.Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism[J].Proc Natl Acad Sci USA,2010,107(24):11074-11079.
[23] Hoeffer CA,Klann E.mTOR signaling:at the crossroads of plasticity,memory and disease[J].Trends Neurosci,2010,33(2):67-75.