基于DNA芯片技术的Reelin信号通路相关基因多态性及基因间交互作用与汉族儿童孤独症关系的研究
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摘要
目的：
(1)研究Reelin信号通路相关基因的多态性与汉族儿童孤独症的关联；
(2)研究Reelin信号通路相关基因的交互作用与汉族儿童孤独症易感性的关系；
(3)研究Reelin信号通路相关基因的多态性与汉族儿童孤独症临床表型的关系。
方法：
(1)采用Illumina CNV 370-Duo芯片对455例符合DSM-IV诊断标准的儿童孤独症患者及97例正常对照进行全基因组SNP分型,从中选取Reelin信号通路6个基因(RELN, DAB1、VLDLR、LRP8、FYN, CDK5)所有SNP的数据,与中南大学医学遗传学国家重点实验室遗传资源库的另外358例正常对照的相应数据合并,对数据进行筛选,然后对每个基因均采用Haploview4.1软件进行单位点的病例-对照关联分析,以及基于连锁不平衡分析基础上的单体型病例-对照关联分析。置换检验被用于对关联分析的结果进行校正(置换次数=1000)。
(2)采用“标记SNP+连锁结构域”策略选择基因间交互作用研究的SNP位点,6个基因共计入选48个位点。多因子降维分析(MDR)方法被用于探索孤独症患者Reelin信号通路相关基因间的交互作用,选择具有最大的交叉验证一致性、最大检验准确度且置换检验结果具有显著性的组合作为基因间交互作用的最佳模型。
(3)剔除15例临床资料不完整的患者,将440例孤独症患者按照“退化”临床表型分为退化组(180例)和非退化组(260例),按照“不遵从行为”临床表型分为不遵从组(177例)和遵从组(263例),χ2检验被用于比较上述48个位点基因型频率和等位基因频率的组间差异。
结果：
(1)经置换检验后,单位点关联分析显示RELN的99个SNPs与孤独症均无显著关联(P均大于0.05)；单体型关联分析发现AAGTATCATGGG单体型频率和CTTAGCCG单体型频率在对照组显著高于孤独症组(χ2分别为8.658,10.000；校正后的P值分别为0.015,0.002)；
(2)经置换检验后,单位点关联分析显示DAB1的154个SNPs与孤独症均无显著关联(P均大于0.05),单体型关联分析发现GGTTTGGCATTTC单体型频率在孤独症组显著高于对照组(χ2=8.461,校正后的P=0.019)；
(3)经置换检验后,LRP8、VLDLR、FYN和CDK5所有SNPs的等位基因频率及单体型频率在孤独症组和对照组无显著性差异(P均大于0.05)；
(4) MDR分析显示三位点基因型组合(rs1454627-rs6943822-rs722187)是孤独症患者Reelin信号通路相关基因间交互作用的最佳模型(交叉验证一致性9/10,检验准确度0.822,P<0.001)；
(5)RELN的rs10487160位点的基因型分布和等位基因分布在退化型孤独症亚组和非退化型孤独症亚组间均存在显著性差异(χ2分别为10.570和10.190,P值分别为0.005和0.001),退化亚组GG基因型频率与G等位基因频率显著高于非退化亚组；rs12666897位点的基因型分布和等位基因分布在两个亚组间亦存在显著性差异(χ2分别为6.019和4.874,P值分别为0.049和0.027),退化亚组AC基因型频率及C等位基因频率显著高于非退化亚组；
(6)RELN的rs17157128位点基因型分布和等位基因分布在不遵从组和遵从组之间有显著性差异(χ2分别为9.165和4.472,P值分别为0.010和0.034),不遵从亚组AA基因型频率和A等位基因频率显著高于遵从亚组；
(7)DAB1的rs3131735位点的基因型分布在不遵从亚组和遵从亚组间存在显著性差异(χ2=8.430,P=0.015),AG基因型频率在不遵从组的显著高于遵从组；
(8) LRP8的rs1288520位点基因型分布和等位基因分布在退化组和非退化组之间有显著性差异(χ2分别为7.790和7.095,P值分别为0.020和0.008),GG基因型频率和G等位基因频率在退化亚组显著高于非退化亚组。
(9)VLDLR的rs1454627位点基因型分布和等位基因分布在退化组和非退化组之间有显著性差异(χ2分别为7.143和4.127,P值分别为0.028和0.042),TT基因型频率和T等位基因频率在退化亚组显著高于非退化亚组；
结论：
(1)RELN可能不是中国汉族儿童孤独症的易感基因,其AAGTATCATGGG单体型和CTTAGCCG单体型反而可能是孤独症的保护因素；
(2)DAB1上的GGTTTGGCATTTC单体型与孤独症存在显著的正性关联,DAB1可能是中国汉族儿童孤独症的易感基因之一；
(3)LRP8、VLDLR、FYN和CDK5的单核甘酸多态性均与中国汉族儿童孤独症无关；
(4)DAB1-RELN-VLDLR基因间交互作用与中国汉族儿童孤独症的发病机制有关；
(5)RELN的rs10487160位点以及rs12666897位点多态性与孤独症患者的“退化”临床表型有关；
(6)RELN的rs17157128位点多态性与孤独症患者的“不遵从行为”临床表型有关；
(7) DAB1的rs3131735位点多态性与孤独症患者的“不遵从行为”临床表型有关；
(8) LPR8的rs1288520位点多态性与孤独症患者的“退化”临床表型有关；
(9)VLDLR的rs1454627位点多态性与孤独症患者的“退化”临床表型有关。
Objective:
(1) To explore the association of reelin-signaling-pathway-related-genes polymorphisms with autism in Chinese Han population.
(2) To explore the relationship between the gene-gene interaction of reelin-signaling-pathway-related-genes and the susceptibility of autism in Chinese Han population.
(3) To explore the relationship between reelin-signaling-pathway-related-genes polymorphisms and the clinical phenotype of autism in Chinese Han population.
Methods:
(1) Genome-wide SNP genotyping was performed using Illumina CNV 370-Duo chip in 455 autistic children fulfilled with DSM-IV-TR criteria for autistic disorder and in 97 healthy controls. SNP data of the six genes in reelin signaling pathway were combined with the corresponding data of additional 358 controls, which was selected randomly from the genetic resource of State Key Laboratory of Medical Genetic of China. Single marker case-control association analysis and haplotype case-control association analysis based on linkage disequilibrium were conducted using Haploview 4.1 software after the data was screened. The significance of results was corrected by permutation test (number of permutation=1000).
(2) 48 SNPs in reeelin-signaling-pathway-related-genes were involved in the analysis of gene-gene interaction using strategy of TagSNP & Linkage Block. Multifactor dimensionality reduction (MDR) was used to detect gene-gene interaction in autistic individuals. Model with the highest CV consistency, the highest testing accuracy as well as the significant permutation test results was considered as the best interaction-model.
(3) The present study excluded 15 autistic individuals with incomplete clinical data.440 patients were divided into regression subgroup (180) and non-regression subgroup (260) according to the presence or absence of regression, alternatively divided into challenging-behavior subgroup (177) and non-challenging-behavior subgroup (263) according to the presence or absence of challenging behaviors. Chi square test was used to compare the inter-group differences of genotypic and allelic distribution to detect the association between polymorphisms of 48 SNPs mentioned above and autistic clinical phenotypes.
Results:
(1) Single marker case-control analysis did not find significant association between all 99 SNPs of RELN with autism after the P value was corrected by permutation test (P>0.05). Haplotype case-control analysis revealed that frequency of AAGTATCATGGG and CTTAGCCG were significantly higher in control group than in autism group after the P value was corrected by permutation test (χ2=8.658,10.000 respectively; P=0.015,0.002 respectively).
(2) Single marker case-control analysis did not find significant association between all 154 SNPs of DAB1 with autism after the P value was corrected by permutation test (P>0.05). Haplotype case-control analysis revealed that frequency of GGTTTGGCATTTC was significantly higher in autism group than in control group after the P value was corrected by permutation test (χ2=8.461,P=0.019).
(3) There were no significant differences in allelic frequency and haplotypic frequency between autism group and control group in all SNPs of LRP8, VLDLR, FYN and CDK5 after the P value was corrected by permutation test (P>0.05).
(4) MDR analysis revealed that the three-loci genotypic combination (rs1454627-rs6943822-rs722187) was the best gene-gene interaction model of reeelin-signaling-pathway-related-genes in the etiology of autism (CV consistency=9/10, testing accuracy=0.822, P<0.001).
(5) Significant differences were found in genotypic and allelic distribution of rs 10487160 within RELN between the regression subgroup and non-regression subgroup (χ2=10.570,10.190 respectively; P=0.005,0.001 respectively), genotypic frequency of GG and allelic frequency of G in regression subgroup were significantly higher than in non-regression subgroup. Significant differences were found in genotypic and allelic distribution of rs12666897 within RELN between the two subgroups (χ2=6.019,4.874 respectively; P=0.049,0.027 respectively), genotypic frequency of AC and allelic frequency of C in regression subgroup were significantly higher than in non-regression subgroup.
(6) Significant differences were found in genotypic and allelic distribution of rs17157128 within RELN between the challenging subgroup and non-challenging subgroup (χ2=9.165,4.472 respectively; P=0.010,0.034 respectively). Genotypic frequency of AA and allelic frequency of A in challenging subgroup were significantly higher than in non-challenging subgroup.
(7) Significant differences were found in genotypic distribution of rs3131735 within DAB1 between the challenging subgroup and non-challenging subgroup (χ2=8.430, P=0.015). Genotypic frequency of AG in challenging subgroup were significantly higher than in non-challenging subgroup.
(8) Significant differences were found in genotypic and allelic distribution of rs1288520 within LRP8 between the regression subgroup and non-regression subgroup (χ2=7.790,7.095 respectively; P=0.020,0.008 respectively). Genotypic frequency of GG and allelic frequency of G in regression subgroup were significantly higher than in non-regression subgroup.
(9) Significant differences were found in genotypic and allelic distribution of rs 1454627 within VLDLR between the regression subgroup and non-regression subgroup (χ2=7.143,4.127 respectively; P=0.028,0.042 respectively). Genotypic frequency of TT and allelic frequency of T in regression subgroup were significantly higher than in non-regression subgroup.
Conclusion:
(1) RELN is not likely to be susceptibility gene of autism. On the contrary, the haplotypes of AAGTATCATGGG and CTTAGCCG may be protective factors for childhood autism in Chinese Han population.
(2) There is a positive association between the DAB1 haplotype of GGTTTGGCATTTC and autism, which suggests that DAB1 may be one of the susceptibility genes of autism in Chinese Han population.
(3) There are no association between polymorphisms of LRP8, VLDLR, FYN, CDK5 and the susceptibility of autism in Chinese Han population.
(4) Gene-gene interaction of DAB1-RELN-VLDLR may be involved in the etiology of autism in Chinese Han population.
(5) Polymorphisms of rs10487160 and rs12666897 within RELN are associated with regression phenotype in autistic individuals.
(6) Polymorphisms of rs17157128 within RELN is associated with challenging behavior phenotype in autistic individuals.
(7) Polymorphisms of rs3131735 within DAB1 is associated with challenging behavior phenotype in autistic individuals.
(8) Polymorphisms of rs1288520 within LRP8 is associated with regression phenotype in autistic individuals.
(9) Polymorphisms of rs1454627 within VLDLR is associated with regression phenotype in autistic individuals.
(1)研究Reelin信号通路相关基因的多态性与汉族儿童孤独症的关联；
(2)研究Reelin信号通路相关基因的交互作用与汉族儿童孤独症易感性的关系；
(3)研究Reelin信号通路相关基因的多态性与汉族儿童孤独症临床表型的关系。
方法：
(1)采用Illumina CNV 370-Duo芯片对455例符合DSM-IV诊断标准的儿童孤独症患者及97例正常对照进行全基因组SNP分型,从中选取Reelin信号通路6个基因(RELN, DAB1、VLDLR、LRP8、FYN, CDK5)所有SNP的数据,与中南大学医学遗传学国家重点实验室遗传资源库的另外358例正常对照的相应数据合并,对数据进行筛选,然后对每个基因均采用Haploview4.1软件进行单位点的病例-对照关联分析,以及基于连锁不平衡分析基础上的单体型病例-对照关联分析。置换检验被用于对关联分析的结果进行校正(置换次数=1000)。
(2)采用“标记SNP+连锁结构域”策略选择基因间交互作用研究的SNP位点,6个基因共计入选48个位点。多因子降维分析(MDR)方法被用于探索孤独症患者Reelin信号通路相关基因间的交互作用,选择具有最大的交叉验证一致性、最大检验准确度且置换检验结果具有显著性的组合作为基因间交互作用的最佳模型。
(3)剔除15例临床资料不完整的患者,将440例孤独症患者按照“退化”临床表型分为退化组(180例)和非退化组(260例),按照“不遵从行为”临床表型分为不遵从组(177例)和遵从组(263例),χ2检验被用于比较上述48个位点基因型频率和等位基因频率的组间差异。
结果：
(1)经置换检验后,单位点关联分析显示RELN的99个SNPs与孤独症均无显著关联(P均大于0.05)；单体型关联分析发现AAGTATCATGGG单体型频率和CTTAGCCG单体型频率在对照组显著高于孤独症组(χ2分别为8.658,10.000；校正后的P值分别为0.015,0.002)；
(2)经置换检验后,单位点关联分析显示DAB1的154个SNPs与孤独症均无显著关联(P均大于0.05),单体型关联分析发现GGTTTGGCATTTC单体型频率在孤独症组显著高于对照组(χ2=8.461,校正后的P=0.019)；
(3)经置换检验后,LRP8、VLDLR、FYN和CDK5所有SNPs的等位基因频率及单体型频率在孤独症组和对照组无显著性差异(P均大于0.05)；
(4) MDR分析显示三位点基因型组合(rs1454627-rs6943822-rs722187)是孤独症患者Reelin信号通路相关基因间交互作用的最佳模型(交叉验证一致性9/10,检验准确度0.822,P<0.001)；
(5)RELN的rs10487160位点的基因型分布和等位基因分布在退化型孤独症亚组和非退化型孤独症亚组间均存在显著性差异(χ2分别为10.570和10.190,P值分别为0.005和0.001),退化亚组GG基因型频率与G等位基因频率显著高于非退化亚组；rs12666897位点的基因型分布和等位基因分布在两个亚组间亦存在显著性差异(χ2分别为6.019和4.874,P值分别为0.049和0.027),退化亚组AC基因型频率及C等位基因频率显著高于非退化亚组；
(6)RELN的rs17157128位点基因型分布和等位基因分布在不遵从组和遵从组之间有显著性差异(χ2分别为9.165和4.472,P值分别为0.010和0.034),不遵从亚组AA基因型频率和A等位基因频率显著高于遵从亚组；
(7)DAB1的rs3131735位点的基因型分布在不遵从亚组和遵从亚组间存在显著性差异(χ2=8.430,P=0.015),AG基因型频率在不遵从组的显著高于遵从组；
(8) LRP8的rs1288520位点基因型分布和等位基因分布在退化组和非退化组之间有显著性差异(χ2分别为7.790和7.095,P值分别为0.020和0.008),GG基因型频率和G等位基因频率在退化亚组显著高于非退化亚组。
(9)VLDLR的rs1454627位点基因型分布和等位基因分布在退化组和非退化组之间有显著性差异(χ2分别为7.143和4.127,P值分别为0.028和0.042),TT基因型频率和T等位基因频率在退化亚组显著高于非退化亚组；
结论：
(1)RELN可能不是中国汉族儿童孤独症的易感基因,其AAGTATCATGGG单体型和CTTAGCCG单体型反而可能是孤独症的保护因素；
(2)DAB1上的GGTTTGGCATTTC单体型与孤独症存在显著的正性关联,DAB1可能是中国汉族儿童孤独症的易感基因之一；
(3)LRP8、VLDLR、FYN和CDK5的单核甘酸多态性均与中国汉族儿童孤独症无关；
(4)DAB1-RELN-VLDLR基因间交互作用与中国汉族儿童孤独症的发病机制有关；
(5)RELN的rs10487160位点以及rs12666897位点多态性与孤独症患者的“退化”临床表型有关；
(6)RELN的rs17157128位点多态性与孤独症患者的“不遵从行为”临床表型有关；
(7) DAB1的rs3131735位点多态性与孤独症患者的“不遵从行为”临床表型有关；
(8) LPR8的rs1288520位点多态性与孤独症患者的“退化”临床表型有关；
(9)VLDLR的rs1454627位点多态性与孤独症患者的“退化”临床表型有关。
Objective:
(1) To explore the association of reelin-signaling-pathway-related-genes polymorphisms with autism in Chinese Han population.
(2) To explore the relationship between the gene-gene interaction of reelin-signaling-pathway-related-genes and the susceptibility of autism in Chinese Han population.
(3) To explore the relationship between reelin-signaling-pathway-related-genes polymorphisms and the clinical phenotype of autism in Chinese Han population.
Methods:
(1) Genome-wide SNP genotyping was performed using Illumina CNV 370-Duo chip in 455 autistic children fulfilled with DSM-IV-TR criteria for autistic disorder and in 97 healthy controls. SNP data of the six genes in reelin signaling pathway were combined with the corresponding data of additional 358 controls, which was selected randomly from the genetic resource of State Key Laboratory of Medical Genetic of China. Single marker case-control association analysis and haplotype case-control association analysis based on linkage disequilibrium were conducted using Haploview 4.1 software after the data was screened. The significance of results was corrected by permutation test (number of permutation=1000).
(2) 48 SNPs in reeelin-signaling-pathway-related-genes were involved in the analysis of gene-gene interaction using strategy of TagSNP & Linkage Block. Multifactor dimensionality reduction (MDR) was used to detect gene-gene interaction in autistic individuals. Model with the highest CV consistency, the highest testing accuracy as well as the significant permutation test results was considered as the best interaction-model.
(3) The present study excluded 15 autistic individuals with incomplete clinical data.440 patients were divided into regression subgroup (180) and non-regression subgroup (260) according to the presence or absence of regression, alternatively divided into challenging-behavior subgroup (177) and non-challenging-behavior subgroup (263) according to the presence or absence of challenging behaviors. Chi square test was used to compare the inter-group differences of genotypic and allelic distribution to detect the association between polymorphisms of 48 SNPs mentioned above and autistic clinical phenotypes.
Results:
(1) Single marker case-control analysis did not find significant association between all 99 SNPs of RELN with autism after the P value was corrected by permutation test (P>0.05). Haplotype case-control analysis revealed that frequency of AAGTATCATGGG and CTTAGCCG were significantly higher in control group than in autism group after the P value was corrected by permutation test (χ2=8.658,10.000 respectively; P=0.015,0.002 respectively).
(2) Single marker case-control analysis did not find significant association between all 154 SNPs of DAB1 with autism after the P value was corrected by permutation test (P>0.05). Haplotype case-control analysis revealed that frequency of GGTTTGGCATTTC was significantly higher in autism group than in control group after the P value was corrected by permutation test (χ2=8.461,P=0.019).
(3) There were no significant differences in allelic frequency and haplotypic frequency between autism group and control group in all SNPs of LRP8, VLDLR, FYN and CDK5 after the P value was corrected by permutation test (P>0.05).
(4) MDR analysis revealed that the three-loci genotypic combination (rs1454627-rs6943822-rs722187) was the best gene-gene interaction model of reeelin-signaling-pathway-related-genes in the etiology of autism (CV consistency=9/10, testing accuracy=0.822, P<0.001).
(5) Significant differences were found in genotypic and allelic distribution of rs 10487160 within RELN between the regression subgroup and non-regression subgroup (χ2=10.570,10.190 respectively; P=0.005,0.001 respectively), genotypic frequency of GG and allelic frequency of G in regression subgroup were significantly higher than in non-regression subgroup. Significant differences were found in genotypic and allelic distribution of rs12666897 within RELN between the two subgroups (χ2=6.019,4.874 respectively; P=0.049,0.027 respectively), genotypic frequency of AC and allelic frequency of C in regression subgroup were significantly higher than in non-regression subgroup.
(6) Significant differences were found in genotypic and allelic distribution of rs17157128 within RELN between the challenging subgroup and non-challenging subgroup (χ2=9.165,4.472 respectively; P=0.010,0.034 respectively). Genotypic frequency of AA and allelic frequency of A in challenging subgroup were significantly higher than in non-challenging subgroup.
(7) Significant differences were found in genotypic distribution of rs3131735 within DAB1 between the challenging subgroup and non-challenging subgroup (χ2=8.430, P=0.015). Genotypic frequency of AG in challenging subgroup were significantly higher than in non-challenging subgroup.
(8) Significant differences were found in genotypic and allelic distribution of rs1288520 within LRP8 between the regression subgroup and non-regression subgroup (χ2=7.790,7.095 respectively; P=0.020,0.008 respectively). Genotypic frequency of GG and allelic frequency of G in regression subgroup were significantly higher than in non-regression subgroup.
(9) Significant differences were found in genotypic and allelic distribution of rs 1454627 within VLDLR between the regression subgroup and non-regression subgroup (χ2=7.143,4.127 respectively; P=0.028,0.042 respectively). Genotypic frequency of TT and allelic frequency of T in regression subgroup were significantly higher than in non-regression subgroup.
Conclusion:
(1) RELN is not likely to be susceptibility gene of autism. On the contrary, the haplotypes of AAGTATCATGGG and CTTAGCCG may be protective factors for childhood autism in Chinese Han population.
(2) There is a positive association between the DAB1 haplotype of GGTTTGGCATTTC and autism, which suggests that DAB1 may be one of the susceptibility genes of autism in Chinese Han population.
(3) There are no association between polymorphisms of LRP8, VLDLR, FYN, CDK5 and the susceptibility of autism in Chinese Han population.
(4) Gene-gene interaction of DAB1-RELN-VLDLR may be involved in the etiology of autism in Chinese Han population.
(5) Polymorphisms of rs10487160 and rs12666897 within RELN are associated with regression phenotype in autistic individuals.
(6) Polymorphisms of rs17157128 within RELN is associated with challenging behavior phenotype in autistic individuals.
(7) Polymorphisms of rs3131735 within DAB1 is associated with challenging behavior phenotype in autistic individuals.
(8) Polymorphisms of rs1288520 within LRP8 is associated with regression phenotype in autistic individuals.
(9) Polymorphisms of rs1454627 within VLDLR is associated with regression phenotype in autistic individuals.
引文
[1]Wing L. The autistic spectrum. Lancet,1997,350(9030):1761-1766.
[2]Ghanizadeh A. A preliminary study on screening prevalence of pervasive developmental disorder in schoolchildren in Iran. J Autism Dev Disord,2008, 38(4):759-763.
[3]McCracken JT, McGough J, Shan B, et al. Risperidon in children with autism and serious behavioral problems. N Engl J Med,2002,347(5):314-321.
[4]Gencer O, Emiroglu FN, Miral S, et al. Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder:an open label maintenance study. Eur Child Adolesc Psychiatry,2008, 17(4):217-225.
[5]Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology,2002,46(2):76-84.
[6]Wilkerson DS, Volpe AG, Dean RS, et al. Perinatal complications as predictors of infantile autism. Int J Neurosci,2002,112(9):1085-1098.
[7]Nelson PG, Kuddo T, Song EY, et al. Selected neurotrophins, neuropeptide, and cytokines:developmental trajectory and concentratios in neonatal blood of children with autism and Down syndrome. Int J Devl Neurosci,2006,24(1):73-80.
[8]Scott MM, Deneris ES. Making and breaking serotonin neurons and autism. Int J Devl Neurosci,2005,23(2-3):277-285.
[9]Aldred S, Moore KM, Fitzgerald M, et al. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord,2003,33(1):93-97.
[10]Sundaram SK, Kumar A, Makki MI, et al. Diffusin tensor imaging of frontal lobe in autism spectrum disorder. Cereb Cortex,2008,18(11):2659-2665.
[11]Szatmari P, Jones MB, Zwaigenbaum L, et al. Genetics of autism:overview and new directions. J Autism Dev Disord,1998,28(5):351-368.
[12]Greenberg DA, Hodge SE, Sowinski J, et al. Excess of twins among affected sibling pairs with autism:implications for the etiology of autism. Am J Hum Genet,2001,69(5):1062-1067.
[13]Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins & the Autism Consortium, et al. A genome-wide linkage and association scan reveals novel loci for autism. Nature,2009,461(7265):802-808.
[14]Philippe A, Guilloud-Bataille M, Martinez M, et al. Analysis of ten candidate genes in autism by associatoin and linkage. Am J Med Genet,2002,114(2): 125-128.
[15]Schellenberg GD, Dawson G, Sung YJ, et al. Evidence for multiple loci from a genome scan of autism kindreds. Mol Psychiatry,2006,11 (11):1049-1060.
[16]Gupta AR, State MW. Recent advances in the genetics of autism. Biol Psychiatry,2007,61(4):429-437.
[17]Abrahams BS, Geschwind DH. Advances in autism genetics:on the threshold of a new neurobiology. Nat Rev Genet,2008,9(5):341-355.
[18]Sadakata T, Washida M, Iwayama Y, et al. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest,2007,117(4):931-943.
[19]Ashley-Koch AE, Jaworski J, Ma de Q, et al. Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk. Psychiatr Genet,2007,17(4):221-226.
[20]Skaar DA, ShaoY, Haines JL, et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry,2005,10(6):563-571.
[21]Shao Y, Cuccaro ML, Hauser ER, et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotype subtypes. Am J Hum Genet,2003, 72(3):539-548.
[22]McCauley JL, Olson LM, Delahanty R, et al. A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet,2004,131B(1):51-59.
[23]Wang K, Zhang H, Ma D, et al. Common genetic variants on 5p14.1 associate with autism sepctrum disorders. Nature,2009,459(7246):528-533.
[24]Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis,2008,3:30-37.
[25]Sing CF, Stengard JH, Kardia SL. Genes, environment, and cardiovascular disease. Arterioscler Thromb Vase Biol,2003,23(7):1190-1196.
[26]Moore JH. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered,2003,56(1-3):73-82.
[27]Santangelo S, Folstein S. The genetics of autism. In:Tager-Flusberg H. (Ed.) Neurodevelopmental disorders. Cambridge MA:MT press,1999:431-447.
[28]Blohm DH, Guiseppi-Elie A. New developments in microarray technology. Curr Opin Biotechnol,2001,12(1):41-47.
[29]Ma D, Salyakina D, Jaworski JM, et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet, 2009,73(Pt 3):263-73.
[30]Fatemi SH, Stary JM, Egan EA. Reduced blood levels of Reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol, 2002,22(2):139-152.
[31]Benhayon D, Magdaleno S, Curran T. Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Brain Res Mol Brain Res,2003,112(1-2):33-45.
[32]International Molecular Genetic Study of Autism Consortium (IMGSAC). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet,1998,7(3):571-578.
[33]International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism:strong evidence for linkage to chromosome 2q, 7q and 16q. Am J Hum Genet,2001,69(3):570-581.
[34]American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Fourth edition-text revison. Washington, DC:American Psychiatric Association Press,2000:70-72.
[35]孤独症行为评定量表.张作记主编：行为医学量表手册.北京：中华医学电 子音像出版社,2005,470-471.
[36]儿童孤独症评定量表.张作记主编：行为医学量表手册.北京：中华医学电子音像出版社,2005,476-477.
[37]卢建平,杨志伟,舒明耀,等.儿童孤独症量表的信度效度分析.中国现代医学杂志,2004,14(13)：119-121,123.
[38]王瑜,王玉玮,申永帆.孤独症患儿智力和行为障碍分析.中国儿童保健杂志,2003,11(2)：133-134.
[39]Gunderson KL, Kruglyak S, Graige MS, et al. Decoding randomly ordered DNA arrays. Genome Res,2004,14(5):870-877.
[40]Shen R, Fan JB, Campbell D, et al. High-throughput SNP genotyping on universal bead arrays. Mutat Res,2005,573 (1-2):70-82.
[41]Hashmi G, Shariff T, Seul M, et al. A flexible array format for large-scale, rapid blood group DNA typing. Transfusion,2005,45(5):680-688.
[42]International HapMap consortium. A haplotype map of the human genome. Nature,2005,437(7063):1299-1320.
[43]International HapMap consortium, Frazer KA, Ballinger DG, et al. A second generation human haplotype map of over 3.1 millions SNPs. Nature,2007, 449(7164):851-861.
[44]Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health,2007,28:235-258.
[45]Klauck SM. Genetics of autism spectrum disorder. Eur J Hum Genet,2006, 14(6):714-720.
[46]International Molecular Genetic Study of Autism Consortium (IMGSAC). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet,2001,10(9):973-982.
[47]Collaborative Linkages Study of Autism. Incorporating language phenotypes strengthens evidence of linkage to sutism. Am J Med Genet,2001,105(8): 539-547.
[48]Fatemi SH, Stary JM, Halt AR, et al. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord,2001,31(6):529-535.
[49]Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet,2000,26(1):93-96.
[50]Goffinet AM. Events governing organization of postmigratory neurons:studies on brain development in normal and reeler mice. Brain Research,1984,319(3): 261-296.
[51]Keavney B. Genetic association studies in complex diseases. J Hum Hypertens, 2000,14(6):361-367.
[52]Persico AM, D'Agruma L, Maiorano N, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry,2001, 6(2):150-159.
[53]Dutta S, Guhathakurta S, Sinha S, et al. Reelin gene polymorphisms in the India population:a possible paternal 5'-UTR-CGG-repeat-allele effect on autism. Am J Med Genet B Neuropsychiatr Genet,2007,144B(1):106-112.
[54]Devlin B, Bennett P, Dawson G, et al. Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Am J Med Genet B Neuropsychiatr Genet,2004,126B(1):46-50.
[55]Krebs MO, Betancur C, Leroy S, et al. Absence of association between a polymorphic GGC repeat in the 51 untranslated region of the reelin gene and autism. Mol Psychiatry,2002,7(7):801-804.
[56]Serajee FJ, Zhong H, Mahbubul Huq AH. Association of reelin gene polymorphisms with autism. Genomics,2006,87(1):75-83.
[57]Li H, Li Y, Shao J, et al. The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet,2008,147B(2):194-200.
[58]Pritchard JK, Przeworski M. Linkage disequilibrium in humans:models and data. Am J Hum Genet,2001,69(1):1-14.
[59]Dutta S, Sinha S, Ghosh S, et al. Genetic analysis of reelin gene (RELN) SNPs: No association with autism spectrum disorder in the Indian population. Neurosci Lett,2008,441(1):56-60.
[60]Graus-Porta D, Blaess S, Senften M, et al. Beta 1-class integrin regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron, 2001,31(3):367-379.
[61]Bock HH, Jossin Y, May P, et al. Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein Disabled 1. J Biol Chem,2004,279(32):33471-33479.
[62]Morimura T, Hattori M, Ogawa M, et al. Disabled 1 regulates the intracellular trafficking of reelin receptors. J Biol Chem,2005,280(17):16901-16908.
[63]Fatemi SH, Snow AV, Stary JM, et al. Reelin signaling is impaired in autism. Biol Psychiatry,2005,57(7):777-787.
[64]Hiesberger T, Trommsdorff M, Howell BW, et al. Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron,1999,24(2):481-489.
[65]Barr AM, Fish KN, Markou A. The reelin receptors VLDLR and ApoER2 regulate sensorimotor gating in mice. Neuropharmacology,2007,52(4):1114-1123.
[66]Hibi T, Mizutani M, Baba A, et al. Splicing variations in the ligand-binding domain of ApoER2 results in functional differences in the binding properties of reelin. Neurosci Res,2009,63(4):251-258.
[67]Hosoda A, Inoue T, Mao CC, et al. Polymorphisms in the human apolipoprotein E receptor 2 gene in Japanses sporadic Alzheimer's disease patients. Biosci Biotechnol Biochem,2010,74(3):677-679.
[68]Bock HH, Herz J. Reelin avtivates Src family tyrosine kinases in neurons. Curr Biol,2003,13(1):18-26.
[69]Arnaud L, Ballif BA, Forster E, et al. Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr Biol,2003,13(1):9-17.
[70]Lalioti V, Pulido D, Sandoval IV. Cdk5, the multifunctional surveyor. Cell Cycle, 2010,9(2):284-311.
[71]Choi HS, Lee Y, Park KH, et al. Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. J Hum Genet,2009,54(5):298-303.
[72]Gupta A, Tsai LH. Cyclin-dependent kinase 5 and neuronal migration in the neocortex. Neurosignals,2003,12(4-5):173-179.
[73]Xie Z, Samuels BA, Tsai LH. Cyclin-dependent kinase 5 permits efficient cytoskeletal remodeling-a hypothesis on neuronal migration. Cereb Cortex, 2006,16(Supl 1):i64-68.
[74]Ohshima T, Suzuki H, Morimura T, et al. Modulation of Reelin signaling by Cyclin-dependent kinase 5. Brain Res,2007,1140:84-95.
[75]Keshvara L, Magdaleno S, Benhayon D, et al. Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin gene. J Neurosci,2002, 22(12):4869-4877.
[76]智联腾,周钢桥,贺福初.人类复杂疾病关联分析研究中群体分层的检出和校正.遗传,2007,29(1)：3-7.
[77]Noh JS, Sharma RP, Veldic M, et al. DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci USA, 2005,102(5):1749-1754.
[78]Liu X, Li Y, Wang L, et al. Interaction among genetic variants from SREBP2 activating-related pathway on risk of coronary heart disease in Han population. Atherosclerosis,2010,208(2):421-426.
[79]Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics,2003,19(3):376-382.
[80]Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med,2002,34(2):88-95.
[81]Ritchie MD, Hahn LW, Roodi N, et al. Mutifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet,2001,69(1):138-147.
[82]Nelson MR, Kardia SL, Ferrell RE, et al. A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation. Genome Res,2001, 11(3):458-470.
[83]Moore JH. Computational analysis of gene-gene interactions using multifactor dimensionality reduction. Expert Rev Mol Diagn,2004,4(6):795-803.
[84]Coffey CS, Hebert PR, Krumholz HM, et al. Reporting of model validation procedures in human studies of genetic interactions. Nutrition,2004,20(1):69-73.
[85]Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol,1996, 49(12):1373-1379.
[86]Ritchie MD, Hahn LW, Moore JH. Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol, 2003,24(2):150-157.
[87]Julia A, Moore J, Miquel L, et al. Identification of a two-loci epistatic interaction associated with susceptibility to rheumatoid arthritis through reverse engineering and multifactor dimensionality reduction. Genomics,2007,90(1): 6-13.
[88]Lin E, Hong CJ, Hwang JP, et al. Gene-gene interaction of the brain-derived neurotrophic-factor and neurotrophic tyrosine kinase receptor 2 genes in geriatric depression. Rejuvenation Res,2009,12(6):387-393.
[89]Lin E, Chen PS, Chang HH, et al. Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry,2009,33(7):1167-1172.
[90]Edwards TL, Wang X, Chen Q, et al. Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia. Schizophr Res,2008,106(2-3): 208-217.
[91]Ma DQ, Whitehead PL, Menold MM, et al. Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet,2005,77(3):377-388.
[92]Trommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell,1999,97(6):689-701.
[93]Martin ER, Ritchie MD, Hahn L, et al. A novel menthod to identify gene-gene effects in nuclear families:the MDR-PDT. Genet Epidemiol,2006,30(2):111-123.
[94]Bush WS, Dudek SM, Ritchie MD. Parallel multifactor dimensionality reduction:a tool for the large-scale analysis of gene-gene interaction. Bioinformatics,2006,22(17):2173-2174.
[95]Moore JH, Gilbert JC, Tsai CT, et al. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol,2006,241(2): 252-261.
[96]Goldberg WA, Osann K, Filipek PA, et al. Language and other regression: assessment and timing. J Autism Dev Disord,2003,33(6):607-616.
[97]Nicholas JS, Charles JM, Carpenter LA, et al. Prevalence and characteristics of children with autism-spectrum disorders. Ann Epidemiol,2008,18(2):130-136.
[98]Ronald A, Happe F, Bolton P, et al. Genetic heterogeneity between the three components of the autism spectrum:a twin study. J Am Acad Child Adolesc Psychiatry,2006,45(6):691-699.
[99]Andres C. Molecular genetics and animal models in autistic disorder. Brain Res Bull,2002,57(1):109-119.
[100]Silverman JM, Smith CJ, Schmeidler J, et al. Symptom domains in autism and related conditions:evidence for familiality. Am J Med Genet,2002,114(1):64-73.
[101]Alarcon M, Cantor RM, Liu J, et al. Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet,2002, 70(1):60-71.
[102]Alarcon M, Yonan AL, Gilliam TC, et al. Quantitative genome scan and ordered-subsets analysis of autism endophenotypes support language QTLs. Mol Psychiatry,2005,10(8):747-757.
[103]Spence SJ, Cantor RM, Chung L, et al. Stratification based on language-related endophenotypes in autism:Attempt to replicate linkage. Am J Med Genet B Neuropsychiatr Genet,2006,141B(6):591-598.
[104]Molloy CA, Keddache M, Martin LJ. Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry, 2005,10(8):741-746.
[105]Mazefsky CA, Goin-Kochel RP, Riley BP, et al. Genetic and environmental influences on symptom domains in twins and siblings with autism. Res Autism Spectr Disord,2008,2(2):320-331.
[106]Hansen RL, Ozonoff S, Krakowiak P, et al. Regression in autism:prevalence and associated factors in the CHARGE study. Ambul Pediatr,2008,8(1):25-31.
[107]Lord C, Shulman C, Dilavore P. Regression and word loss in autistic spectrum disorders. J Child Psychol Psychiatry,2004,45(5):936-955.
[108]Burack JA, Volkmar FR. Development of low-and high-functioning autistic children. J Child Psychol Psychiatry,1992,33(3):607-616.
[109]Kobayashi R, Murata T. Setback phenomenon in autism and long-term prognosis. Acta Psychiatr Scand,1998,98(4):296-303.
[110]Brown J, Prelock PA. The impact of regression on language development in autism. J Autism Dev Disord,1995,25(3):305-309.
[111]McDougle CJ, Stigler KA, Erickson CA, et al. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry,2008,69 (suppl 4):15-20.
[112]Chavez B, Chavez-Brown M, Sopko MA Jr, et al. Atypical antipsychotics in children with pervasive developmental disorders. Paediatr Drugs,2007,9(4): 249-266.
[113]Yoo HJ, Cho IH, Park M, et al. Association between PTGS2 polymorphism and autism spectrum disorders in Korean trios. Neurosci Res,2008,62(1):66-69.
[114]Brune CW, Kim SJ, Salt J, et al.5-HTTLPR genotype-specific phenotype in children and adolescents with autism. Am J Psychiatry,2006,163(12):2148-2156.
[1]Weeber EJ, Beffert U, Jones C, et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem,2002,277 (42):39944-39952.
[2]D'Arcangelo G. Apoer2:a reelin receptor to remember. Neuron,2005,47(4): 471-473.
[3]Hamburgh M. Analysis of the postnatal developmental effects of "reeler", a neurological mutation in mice. A study in developmental genetics. Dev Biol, 1963,19:165-185.
[4]Miao GG, Smeyne RJ, D'Arcangelo G, et al. Isolation of an allele of reeler by insertional mutagenesis. Proc Natl Acad Sci USA,1994,91 (23):11050-11054.
[5]D'Arcangelo G, Miao GG, Chen SC, et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature,1995,374 (6524): 719-723.
[6]Meyer G, Goffinet AM, Fairen A. What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex. Cereb Cortex,1999,9 (8):765-775.
[7]Hack I, Bancila M, Loulier K, et al. Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nat Neurosci,2002,5(10):939-945.
[8]Yip YP, Mehta N, Magdaleno S, et al. Ectopic expression of reelin alters migration of sympathetic preganglionic neurons in the spinal cord. J Comp Neurol,2009,515 (2):260-268.
[9]Wang GS, Hong CJ, Yen TY, et al. Transcriptional modification by a CASK-interacting nucleosome assembly protein. Neuron,2004,42 (1):113-128.
[10]Lintas C, Persico AM. Neocortical RELN promoter methylation increases significantly after puberty. Neuroreport,2010,21 (2):114-118.
[11]Dong E, Nelson M, Grayson DR, et al. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci USA,2008,105(36):13614-13619.
[12]Fatemi SH. Reelin Glycoprotein:Structure, Biology and Roles in Health and Disease. Mol Psychiatry,2005,10(3):251-257.
[13]Fatemi SH, Reutiman TJ, Folsom TD. Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats. Schizophr Res,2009,111(1-3):138-152.
[14]Trommsdorff M, Borg JP, Margolis B, et al. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J Biol Chem,1998,273 (50):33556-33560.
[15]Trommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell,1999,97 (6):689-701.
[16]Sheldon M, Rice DS, D'Arcangelo G, et al. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature,1997,389 (6652):730-733.
[17]Hack I, Hellwig S, Junghans D, et al. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development,2007,134 (21):3883-3891.
[18]Schmid RS, Jo R, Shelton S, et al. Reelin, integrin and DAB1 interactions during embryonic cerebral cortical development. Cereb Cortex,2005,15 (10):1632-1636.
[19]Senzaki K, Ogawa M, Yagi T. Proteins of the CNR family are multiple receptors for Reelin. Cell,1999,99(6):635-647.
[20]Jossin Y, Ignatova N, Hiesberger T, et al. The central fragment of Reelin, generated by proteolytic processing in vivo, is critical to its function during cortical plate development. J Neurosci,2004,24 (2):514-521.
[21]Chai X, Forster E, Zhao S, et al. Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3. J Neurosci, 2009,29 (1):288-299.
[22]Frotscher M, Chai X, Bock HH, et al. Role of Reelin in the development and maintenance of cortical lamination. J Neural Transm,2009,116(11):1451-1455.
[23]Feng L, Allen NS, Simo S, et al. Cullin 5 regulates Dabl protein levels and neuron positioning during cortical development. Genes Dev,2007,21(21):2717-2730.
[24]Kerjan G, Gleeson JG. A missed exit:Reelin sets in motion Dabl polyubiquitination to put the break on neuronal migration. Genes Dev,2007,21 (22):2850-2854.
[25]Strasser V, Fasching D, Hauser C, et al. Receptor clustering is involved in Reelin signaling. Mol Cell Biol,2004,24 (3):1378-1386.
[26]Matsuki T, Pramatarova A, Howell BW. Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis. J Cell Sci,2008,121 (Pt 11):1869-1875.
[27]Ballif BA, Arnaud L, Arthur WT, et al. Activation of a Dabl/CrkL/C3G/Rapl pathway in Reelin-stimulated neurons. Curr Biol,2004,14 (7):606-610.
[28]Park TJ, Curran T. Crk and crk-like play essential overlapping roles downstream of disabled-1 in the reelin pathway. J Neurosci,2008,28 (50):13551-13562.
[29]Arnaud L, Ballif BA, Cooper JA. Regulation of protein tyrosine kinase signaling by substrate degradation during brain development. Mol Cell Biol,2003,23 (24): 9293-9302.
[30]Ohshima T, Suzuki H, Morimura T, et al. Modulation of Reelin signaling by Cyclin-dependent kinase 5. Brain Res,2007,1140:84-95.
[31]Keshvara L, Magdaleno S, Benhayon D, et al. Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling. J Neurosci,2002, 22 (12):4869-4877.
[32]Kobayashi S, Ishiguro K, Omori A, et al. A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS Lett,1993,335 (2):171-175.
[33]Beffert U, Weeber EJ, Morfini G, et al. Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission. J Neurosci,2004,24 (8):1897-1906.
[34]Ohshima T, Ogawa M, Veeranna, et al. Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dabl to the positioning of cortical neurons in the developing mouse brain. Proc Natl Acad Sci USA,2001,98 (5): 2764-2769.
[35]Zhang G, Assadi AH, McNeil RS, et al. The pafahlb complex interacts with the reelin receptor VLDLR. PloS One,2007,2(2):e252.
[36]International Molecular Genetic Study of Autism Consortium (IMGSAC). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet,1998,7(3):571-578.
[37]International Molecular Genetic Study of Autism Consortium (IMGSAC). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet,2001,10(9):973-982.
[38]Yonan AL, Alarcon M, Cheng R, et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet,2003,73(4):886-897.
[39]Fatemi SH, Halt AR, Realmuto G, et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol,2002,22(2):171-175.
[40]Sparks BF, Friedman SD, Shaw DW, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology,2002,59(2):184-192.
[41]Salinger WL,Ladrow P, Wheeler C. Behavioral phenotype of the reeler mutant mouse:effects of RELN gene dosage and social isolation. Behav. Neurosci,2003, 117(6):1257-1275.
[42]Persico AM, D'Agruma L, Maiorano N, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry,2001,6(2):150-159.
[43]Zhang H, Liu X, Zhang C, et al. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry,2002,7(9):1012-1017.
[44]Bonora E, Beyer KS, Lamb JA, et al. Analysis of reelin as a candidate gene for autism. Mol Psychiatry,2003,8(10):885-892.
[45]Devlin B, Bennett P, Dawson G, et al. Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Am J Med Genet B Neuropsychiatr Genet,2004,126B(1):46-50.
[46]Li J, Nguyen L, Gleason C, et al. Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. Am J Med Genet B Neuropsychiatr Genet,2004,126B(1):51-57.
[47]Skaar DA, Shao Y, Haines JL, et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry,2005,10(6):563-571.
[48]Ashley-Koch AE, Jaworski J, Ma DQ, et al. Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk. Psychiatr Genet,2007,17(4):221-226.
[49]Serajee FJ, Zhong H, Mahbubul Huq AH. Association of reelin gene polymorphisms with autism. Genomics,2006,87(1):75-83.
[50]Li H, Li Y, Shao J, et al. The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet,2008,147B(2):194-200.
[51]Dutta S, Sinha S, Ghosh S, et al. Genetic analysis of reelin gene (RELN) SNPs: No association with autism spectrum disorder in the Indian population. Neurosci Lett,2008,441(1):56-60.
[52]Persico AM, D'Agruma L, Zelante L, et al. Enhanced APOE2 transmission rates in families with autistic probands. Psychaitr Genet,2004,14(2):73-82.
[53]Raiford KL, Shao Y, Allen IC, et al. No association between the APOE gene and autism. Am J Med Genet B Neuropsychiatr Genet,2004,125B(1):57-60.
[2]Ghanizadeh A. A preliminary study on screening prevalence of pervasive developmental disorder in schoolchildren in Iran. J Autism Dev Disord,2008, 38(4):759-763.
[3]McCracken JT, McGough J, Shan B, et al. Risperidon in children with autism and serious behavioral problems. N Engl J Med,2002,347(5):314-321.
[4]Gencer O, Emiroglu FN, Miral S, et al. Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder:an open label maintenance study. Eur Child Adolesc Psychiatry,2008, 17(4):217-225.
[5]Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology,2002,46(2):76-84.
[6]Wilkerson DS, Volpe AG, Dean RS, et al. Perinatal complications as predictors of infantile autism. Int J Neurosci,2002,112(9):1085-1098.
[7]Nelson PG, Kuddo T, Song EY, et al. Selected neurotrophins, neuropeptide, and cytokines:developmental trajectory and concentratios in neonatal blood of children with autism and Down syndrome. Int J Devl Neurosci,2006,24(1):73-80.
[8]Scott MM, Deneris ES. Making and breaking serotonin neurons and autism. Int J Devl Neurosci,2005,23(2-3):277-285.
[9]Aldred S, Moore KM, Fitzgerald M, et al. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord,2003,33(1):93-97.
[10]Sundaram SK, Kumar A, Makki MI, et al. Diffusin tensor imaging of frontal lobe in autism spectrum disorder. Cereb Cortex,2008,18(11):2659-2665.
[11]Szatmari P, Jones MB, Zwaigenbaum L, et al. Genetics of autism:overview and new directions. J Autism Dev Disord,1998,28(5):351-368.
[12]Greenberg DA, Hodge SE, Sowinski J, et al. Excess of twins among affected sibling pairs with autism:implications for the etiology of autism. Am J Hum Genet,2001,69(5):1062-1067.
[13]Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins & the Autism Consortium, et al. A genome-wide linkage and association scan reveals novel loci for autism. Nature,2009,461(7265):802-808.
[14]Philippe A, Guilloud-Bataille M, Martinez M, et al. Analysis of ten candidate genes in autism by associatoin and linkage. Am J Med Genet,2002,114(2): 125-128.
[15]Schellenberg GD, Dawson G, Sung YJ, et al. Evidence for multiple loci from a genome scan of autism kindreds. Mol Psychiatry,2006,11 (11):1049-1060.
[16]Gupta AR, State MW. Recent advances in the genetics of autism. Biol Psychiatry,2007,61(4):429-437.
[17]Abrahams BS, Geschwind DH. Advances in autism genetics:on the threshold of a new neurobiology. Nat Rev Genet,2008,9(5):341-355.
[18]Sadakata T, Washida M, Iwayama Y, et al. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest,2007,117(4):931-943.
[19]Ashley-Koch AE, Jaworski J, Ma de Q, et al. Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk. Psychiatr Genet,2007,17(4):221-226.
[20]Skaar DA, ShaoY, Haines JL, et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry,2005,10(6):563-571.
[21]Shao Y, Cuccaro ML, Hauser ER, et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotype subtypes. Am J Hum Genet,2003, 72(3):539-548.
[22]McCauley JL, Olson LM, Delahanty R, et al. A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet,2004,131B(1):51-59.
[23]Wang K, Zhang H, Ma D, et al. Common genetic variants on 5p14.1 associate with autism sepctrum disorders. Nature,2009,459(7246):528-533.
[24]Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis,2008,3:30-37.
[25]Sing CF, Stengard JH, Kardia SL. Genes, environment, and cardiovascular disease. Arterioscler Thromb Vase Biol,2003,23(7):1190-1196.
[26]Moore JH. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered,2003,56(1-3):73-82.
[27]Santangelo S, Folstein S. The genetics of autism. In:Tager-Flusberg H. (Ed.) Neurodevelopmental disorders. Cambridge MA:MT press,1999:431-447.
[28]Blohm DH, Guiseppi-Elie A. New developments in microarray technology. Curr Opin Biotechnol,2001,12(1):41-47.
[29]Ma D, Salyakina D, Jaworski JM, et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet, 2009,73(Pt 3):263-73.
[30]Fatemi SH, Stary JM, Egan EA. Reduced blood levels of Reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol, 2002,22(2):139-152.
[31]Benhayon D, Magdaleno S, Curran T. Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Brain Res Mol Brain Res,2003,112(1-2):33-45.
[32]International Molecular Genetic Study of Autism Consortium (IMGSAC). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet,1998,7(3):571-578.
[33]International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism:strong evidence for linkage to chromosome 2q, 7q and 16q. Am J Hum Genet,2001,69(3):570-581.
[34]American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Fourth edition-text revison. Washington, DC:American Psychiatric Association Press,2000:70-72.
[35]孤独症行为评定量表.张作记主编：行为医学量表手册.北京：中华医学电 子音像出版社,2005,470-471.
[36]儿童孤独症评定量表.张作记主编：行为医学量表手册.北京：中华医学电子音像出版社,2005,476-477.
[37]卢建平,杨志伟,舒明耀,等.儿童孤独症量表的信度效度分析.中国现代医学杂志,2004,14(13)：119-121,123.
[38]王瑜,王玉玮,申永帆.孤独症患儿智力和行为障碍分析.中国儿童保健杂志,2003,11(2)：133-134.
[39]Gunderson KL, Kruglyak S, Graige MS, et al. Decoding randomly ordered DNA arrays. Genome Res,2004,14(5):870-877.
[40]Shen R, Fan JB, Campbell D, et al. High-throughput SNP genotyping on universal bead arrays. Mutat Res,2005,573 (1-2):70-82.
[41]Hashmi G, Shariff T, Seul M, et al. A flexible array format for large-scale, rapid blood group DNA typing. Transfusion,2005,45(5):680-688.
[42]International HapMap consortium. A haplotype map of the human genome. Nature,2005,437(7063):1299-1320.
[43]International HapMap consortium, Frazer KA, Ballinger DG, et al. A second generation human haplotype map of over 3.1 millions SNPs. Nature,2007, 449(7164):851-861.
[44]Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health,2007,28:235-258.
[45]Klauck SM. Genetics of autism spectrum disorder. Eur J Hum Genet,2006, 14(6):714-720.
[46]International Molecular Genetic Study of Autism Consortium (IMGSAC). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet,2001,10(9):973-982.
[47]Collaborative Linkages Study of Autism. Incorporating language phenotypes strengthens evidence of linkage to sutism. Am J Med Genet,2001,105(8): 539-547.
[48]Fatemi SH, Stary JM, Halt AR, et al. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord,2001,31(6):529-535.
[49]Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet,2000,26(1):93-96.
[50]Goffinet AM. Events governing organization of postmigratory neurons:studies on brain development in normal and reeler mice. Brain Research,1984,319(3): 261-296.
[51]Keavney B. Genetic association studies in complex diseases. J Hum Hypertens, 2000,14(6):361-367.
[52]Persico AM, D'Agruma L, Maiorano N, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry,2001, 6(2):150-159.
[53]Dutta S, Guhathakurta S, Sinha S, et al. Reelin gene polymorphisms in the India population:a possible paternal 5'-UTR-CGG-repeat-allele effect on autism. Am J Med Genet B Neuropsychiatr Genet,2007,144B(1):106-112.
[54]Devlin B, Bennett P, Dawson G, et al. Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Am J Med Genet B Neuropsychiatr Genet,2004,126B(1):46-50.
[55]Krebs MO, Betancur C, Leroy S, et al. Absence of association between a polymorphic GGC repeat in the 51 untranslated region of the reelin gene and autism. Mol Psychiatry,2002,7(7):801-804.
[56]Serajee FJ, Zhong H, Mahbubul Huq AH. Association of reelin gene polymorphisms with autism. Genomics,2006,87(1):75-83.
[57]Li H, Li Y, Shao J, et al. The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet,2008,147B(2):194-200.
[58]Pritchard JK, Przeworski M. Linkage disequilibrium in humans:models and data. Am J Hum Genet,2001,69(1):1-14.
[59]Dutta S, Sinha S, Ghosh S, et al. Genetic analysis of reelin gene (RELN) SNPs: No association with autism spectrum disorder in the Indian population. Neurosci Lett,2008,441(1):56-60.
[60]Graus-Porta D, Blaess S, Senften M, et al. Beta 1-class integrin regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron, 2001,31(3):367-379.
[61]Bock HH, Jossin Y, May P, et al. Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein Disabled 1. J Biol Chem,2004,279(32):33471-33479.
[62]Morimura T, Hattori M, Ogawa M, et al. Disabled 1 regulates the intracellular trafficking of reelin receptors. J Biol Chem,2005,280(17):16901-16908.
[63]Fatemi SH, Snow AV, Stary JM, et al. Reelin signaling is impaired in autism. Biol Psychiatry,2005,57(7):777-787.
[64]Hiesberger T, Trommsdorff M, Howell BW, et al. Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron,1999,24(2):481-489.
[65]Barr AM, Fish KN, Markou A. The reelin receptors VLDLR and ApoER2 regulate sensorimotor gating in mice. Neuropharmacology,2007,52(4):1114-1123.
[66]Hibi T, Mizutani M, Baba A, et al. Splicing variations in the ligand-binding domain of ApoER2 results in functional differences in the binding properties of reelin. Neurosci Res,2009,63(4):251-258.
[67]Hosoda A, Inoue T, Mao CC, et al. Polymorphisms in the human apolipoprotein E receptor 2 gene in Japanses sporadic Alzheimer's disease patients. Biosci Biotechnol Biochem,2010,74(3):677-679.
[68]Bock HH, Herz J. Reelin avtivates Src family tyrosine kinases in neurons. Curr Biol,2003,13(1):18-26.
[69]Arnaud L, Ballif BA, Forster E, et al. Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr Biol,2003,13(1):9-17.
[70]Lalioti V, Pulido D, Sandoval IV. Cdk5, the multifunctional surveyor. Cell Cycle, 2010,9(2):284-311.
[71]Choi HS, Lee Y, Park KH, et al. Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. J Hum Genet,2009,54(5):298-303.
[72]Gupta A, Tsai LH. Cyclin-dependent kinase 5 and neuronal migration in the neocortex. Neurosignals,2003,12(4-5):173-179.
[73]Xie Z, Samuels BA, Tsai LH. Cyclin-dependent kinase 5 permits efficient cytoskeletal remodeling-a hypothesis on neuronal migration. Cereb Cortex, 2006,16(Supl 1):i64-68.
[74]Ohshima T, Suzuki H, Morimura T, et al. Modulation of Reelin signaling by Cyclin-dependent kinase 5. Brain Res,2007,1140:84-95.
[75]Keshvara L, Magdaleno S, Benhayon D, et al. Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin gene. J Neurosci,2002, 22(12):4869-4877.
[76]智联腾,周钢桥,贺福初.人类复杂疾病关联分析研究中群体分层的检出和校正.遗传,2007,29(1)：3-7.
[77]Noh JS, Sharma RP, Veldic M, et al. DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci USA, 2005,102(5):1749-1754.
[78]Liu X, Li Y, Wang L, et al. Interaction among genetic variants from SREBP2 activating-related pathway on risk of coronary heart disease in Han population. Atherosclerosis,2010,208(2):421-426.
[79]Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics,2003,19(3):376-382.
[80]Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med,2002,34(2):88-95.
[81]Ritchie MD, Hahn LW, Roodi N, et al. Mutifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet,2001,69(1):138-147.
[82]Nelson MR, Kardia SL, Ferrell RE, et al. A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation. Genome Res,2001, 11(3):458-470.
[83]Moore JH. Computational analysis of gene-gene interactions using multifactor dimensionality reduction. Expert Rev Mol Diagn,2004,4(6):795-803.
[84]Coffey CS, Hebert PR, Krumholz HM, et al. Reporting of model validation procedures in human studies of genetic interactions. Nutrition,2004,20(1):69-73.
[85]Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol,1996, 49(12):1373-1379.
[86]Ritchie MD, Hahn LW, Moore JH. Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol, 2003,24(2):150-157.
[87]Julia A, Moore J, Miquel L, et al. Identification of a two-loci epistatic interaction associated with susceptibility to rheumatoid arthritis through reverse engineering and multifactor dimensionality reduction. Genomics,2007,90(1): 6-13.
[88]Lin E, Hong CJ, Hwang JP, et al. Gene-gene interaction of the brain-derived neurotrophic-factor and neurotrophic tyrosine kinase receptor 2 genes in geriatric depression. Rejuvenation Res,2009,12(6):387-393.
[89]Lin E, Chen PS, Chang HH, et al. Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry,2009,33(7):1167-1172.
[90]Edwards TL, Wang X, Chen Q, et al. Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia. Schizophr Res,2008,106(2-3): 208-217.
[91]Ma DQ, Whitehead PL, Menold MM, et al. Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet,2005,77(3):377-388.
[92]Trommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell,1999,97(6):689-701.
[93]Martin ER, Ritchie MD, Hahn L, et al. A novel menthod to identify gene-gene effects in nuclear families:the MDR-PDT. Genet Epidemiol,2006,30(2):111-123.
[94]Bush WS, Dudek SM, Ritchie MD. Parallel multifactor dimensionality reduction:a tool for the large-scale analysis of gene-gene interaction. Bioinformatics,2006,22(17):2173-2174.
[95]Moore JH, Gilbert JC, Tsai CT, et al. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol,2006,241(2): 252-261.
[96]Goldberg WA, Osann K, Filipek PA, et al. Language and other regression: assessment and timing. J Autism Dev Disord,2003,33(6):607-616.
[97]Nicholas JS, Charles JM, Carpenter LA, et al. Prevalence and characteristics of children with autism-spectrum disorders. Ann Epidemiol,2008,18(2):130-136.
[98]Ronald A, Happe F, Bolton P, et al. Genetic heterogeneity between the three components of the autism spectrum:a twin study. J Am Acad Child Adolesc Psychiatry,2006,45(6):691-699.
[99]Andres C. Molecular genetics and animal models in autistic disorder. Brain Res Bull,2002,57(1):109-119.
[100]Silverman JM, Smith CJ, Schmeidler J, et al. Symptom domains in autism and related conditions:evidence for familiality. Am J Med Genet,2002,114(1):64-73.
[101]Alarcon M, Cantor RM, Liu J, et al. Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet,2002, 70(1):60-71.
[102]Alarcon M, Yonan AL, Gilliam TC, et al. Quantitative genome scan and ordered-subsets analysis of autism endophenotypes support language QTLs. Mol Psychiatry,2005,10(8):747-757.
[103]Spence SJ, Cantor RM, Chung L, et al. Stratification based on language-related endophenotypes in autism:Attempt to replicate linkage. Am J Med Genet B Neuropsychiatr Genet,2006,141B(6):591-598.
[104]Molloy CA, Keddache M, Martin LJ. Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry, 2005,10(8):741-746.
[105]Mazefsky CA, Goin-Kochel RP, Riley BP, et al. Genetic and environmental influences on symptom domains in twins and siblings with autism. Res Autism Spectr Disord,2008,2(2):320-331.
[106]Hansen RL, Ozonoff S, Krakowiak P, et al. Regression in autism:prevalence and associated factors in the CHARGE study. Ambul Pediatr,2008,8(1):25-31.
[107]Lord C, Shulman C, Dilavore P. Regression and word loss in autistic spectrum disorders. J Child Psychol Psychiatry,2004,45(5):936-955.
[108]Burack JA, Volkmar FR. Development of low-and high-functioning autistic children. J Child Psychol Psychiatry,1992,33(3):607-616.
[109]Kobayashi R, Murata T. Setback phenomenon in autism and long-term prognosis. Acta Psychiatr Scand,1998,98(4):296-303.
[110]Brown J, Prelock PA. The impact of regression on language development in autism. J Autism Dev Disord,1995,25(3):305-309.
[111]McDougle CJ, Stigler KA, Erickson CA, et al. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry,2008,69 (suppl 4):15-20.
[112]Chavez B, Chavez-Brown M, Sopko MA Jr, et al. Atypical antipsychotics in children with pervasive developmental disorders. Paediatr Drugs,2007,9(4): 249-266.
[113]Yoo HJ, Cho IH, Park M, et al. Association between PTGS2 polymorphism and autism spectrum disorders in Korean trios. Neurosci Res,2008,62(1):66-69.
[114]Brune CW, Kim SJ, Salt J, et al.5-HTTLPR genotype-specific phenotype in children and adolescents with autism. Am J Psychiatry,2006,163(12):2148-2156.
[1]Weeber EJ, Beffert U, Jones C, et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem,2002,277 (42):39944-39952.
[2]D'Arcangelo G. Apoer2:a reelin receptor to remember. Neuron,2005,47(4): 471-473.
[3]Hamburgh M. Analysis of the postnatal developmental effects of "reeler", a neurological mutation in mice. A study in developmental genetics. Dev Biol, 1963,19:165-185.
[4]Miao GG, Smeyne RJ, D'Arcangelo G, et al. Isolation of an allele of reeler by insertional mutagenesis. Proc Natl Acad Sci USA,1994,91 (23):11050-11054.
[5]D'Arcangelo G, Miao GG, Chen SC, et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature,1995,374 (6524): 719-723.
[6]Meyer G, Goffinet AM, Fairen A. What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex. Cereb Cortex,1999,9 (8):765-775.
[7]Hack I, Bancila M, Loulier K, et al. Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nat Neurosci,2002,5(10):939-945.
[8]Yip YP, Mehta N, Magdaleno S, et al. Ectopic expression of reelin alters migration of sympathetic preganglionic neurons in the spinal cord. J Comp Neurol,2009,515 (2):260-268.
[9]Wang GS, Hong CJ, Yen TY, et al. Transcriptional modification by a CASK-interacting nucleosome assembly protein. Neuron,2004,42 (1):113-128.
[10]Lintas C, Persico AM. Neocortical RELN promoter methylation increases significantly after puberty. Neuroreport,2010,21 (2):114-118.
[11]Dong E, Nelson M, Grayson DR, et al. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci USA,2008,105(36):13614-13619.
[12]Fatemi SH. Reelin Glycoprotein:Structure, Biology and Roles in Health and Disease. Mol Psychiatry,2005,10(3):251-257.
[13]Fatemi SH, Reutiman TJ, Folsom TD. Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats. Schizophr Res,2009,111(1-3):138-152.
[14]Trommsdorff M, Borg JP, Margolis B, et al. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J Biol Chem,1998,273 (50):33556-33560.
[15]Trommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell,1999,97 (6):689-701.
[16]Sheldon M, Rice DS, D'Arcangelo G, et al. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature,1997,389 (6652):730-733.
[17]Hack I, Hellwig S, Junghans D, et al. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development,2007,134 (21):3883-3891.
[18]Schmid RS, Jo R, Shelton S, et al. Reelin, integrin and DAB1 interactions during embryonic cerebral cortical development. Cereb Cortex,2005,15 (10):1632-1636.
[19]Senzaki K, Ogawa M, Yagi T. Proteins of the CNR family are multiple receptors for Reelin. Cell,1999,99(6):635-647.
[20]Jossin Y, Ignatova N, Hiesberger T, et al. The central fragment of Reelin, generated by proteolytic processing in vivo, is critical to its function during cortical plate development. J Neurosci,2004,24 (2):514-521.
[21]Chai X, Forster E, Zhao S, et al. Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3. J Neurosci, 2009,29 (1):288-299.
[22]Frotscher M, Chai X, Bock HH, et al. Role of Reelin in the development and maintenance of cortical lamination. J Neural Transm,2009,116(11):1451-1455.
[23]Feng L, Allen NS, Simo S, et al. Cullin 5 regulates Dabl protein levels and neuron positioning during cortical development. Genes Dev,2007,21(21):2717-2730.
[24]Kerjan G, Gleeson JG. A missed exit:Reelin sets in motion Dabl polyubiquitination to put the break on neuronal migration. Genes Dev,2007,21 (22):2850-2854.
[25]Strasser V, Fasching D, Hauser C, et al. Receptor clustering is involved in Reelin signaling. Mol Cell Biol,2004,24 (3):1378-1386.
[26]Matsuki T, Pramatarova A, Howell BW. Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis. J Cell Sci,2008,121 (Pt 11):1869-1875.
[27]Ballif BA, Arnaud L, Arthur WT, et al. Activation of a Dabl/CrkL/C3G/Rapl pathway in Reelin-stimulated neurons. Curr Biol,2004,14 (7):606-610.
[28]Park TJ, Curran T. Crk and crk-like play essential overlapping roles downstream of disabled-1 in the reelin pathway. J Neurosci,2008,28 (50):13551-13562.
[29]Arnaud L, Ballif BA, Cooper JA. Regulation of protein tyrosine kinase signaling by substrate degradation during brain development. Mol Cell Biol,2003,23 (24): 9293-9302.
[30]Ohshima T, Suzuki H, Morimura T, et al. Modulation of Reelin signaling by Cyclin-dependent kinase 5. Brain Res,2007,1140:84-95.
[31]Keshvara L, Magdaleno S, Benhayon D, et al. Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling. J Neurosci,2002, 22 (12):4869-4877.
[32]Kobayashi S, Ishiguro K, Omori A, et al. A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS Lett,1993,335 (2):171-175.
[33]Beffert U, Weeber EJ, Morfini G, et al. Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission. J Neurosci,2004,24 (8):1897-1906.
[34]Ohshima T, Ogawa M, Veeranna, et al. Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dabl to the positioning of cortical neurons in the developing mouse brain. Proc Natl Acad Sci USA,2001,98 (5): 2764-2769.
[35]Zhang G, Assadi AH, McNeil RS, et al. The pafahlb complex interacts with the reelin receptor VLDLR. PloS One,2007,2(2):e252.
[36]International Molecular Genetic Study of Autism Consortium (IMGSAC). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet,1998,7(3):571-578.
[37]International Molecular Genetic Study of Autism Consortium (IMGSAC). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet,2001,10(9):973-982.
[38]Yonan AL, Alarcon M, Cheng R, et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet,2003,73(4):886-897.
[39]Fatemi SH, Halt AR, Realmuto G, et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol,2002,22(2):171-175.
[40]Sparks BF, Friedman SD, Shaw DW, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology,2002,59(2):184-192.
[41]Salinger WL,Ladrow P, Wheeler C. Behavioral phenotype of the reeler mutant mouse:effects of RELN gene dosage and social isolation. Behav. Neurosci,2003, 117(6):1257-1275.
[42]Persico AM, D'Agruma L, Maiorano N, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry,2001,6(2):150-159.
[43]Zhang H, Liu X, Zhang C, et al. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry,2002,7(9):1012-1017.
[44]Bonora E, Beyer KS, Lamb JA, et al. Analysis of reelin as a candidate gene for autism. Mol Psychiatry,2003,8(10):885-892.
[45]Devlin B, Bennett P, Dawson G, et al. Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Am J Med Genet B Neuropsychiatr Genet,2004,126B(1):46-50.
[46]Li J, Nguyen L, Gleason C, et al. Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. Am J Med Genet B Neuropsychiatr Genet,2004,126B(1):51-57.
[47]Skaar DA, Shao Y, Haines JL, et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry,2005,10(6):563-571.
[48]Ashley-Koch AE, Jaworski J, Ma DQ, et al. Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk. Psychiatr Genet,2007,17(4):221-226.
[49]Serajee FJ, Zhong H, Mahbubul Huq AH. Association of reelin gene polymorphisms with autism. Genomics,2006,87(1):75-83.
[50]Li H, Li Y, Shao J, et al. The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet,2008,147B(2):194-200.
[51]Dutta S, Sinha S, Ghosh S, et al. Genetic analysis of reelin gene (RELN) SNPs: No association with autism spectrum disorder in the Indian population. Neurosci Lett,2008,441(1):56-60.
[52]Persico AM, D'Agruma L, Zelante L, et al. Enhanced APOE2 transmission rates in families with autistic probands. Psychaitr Genet,2004,14(2):73-82.
[53]Raiford KL, Shao Y, Allen IC, et al. No association between the APOE gene and autism. Am J Med Genet B Neuropsychiatr Genet,2004,125B(1):57-60.