摘要
目的:孤独症是一种病因未明的神经发育性疾病,患者临床异质性过高是目前孤独症病因研究面临的主要问题之一。本研究根据儿童孤独症患者语言发育情况建立分类模型,利用其降低异质性,探讨孤独症患者语言发育与RELN信号通路基因(RELN、VLDLR、LRP8、DAB1、CDK5、FYN)单核苷酸多态性的关系。方法:本研究病例组儿童招募自湖南、山东、河南三省共5个医疗及自闭症培训机构,依据招募先后分为两部分(第1部分为训练样本,招募时间为2006年10月至2011年5月,第2部分为验证样本,招募时间为2011年7月至2012年5月)。将孤独症患者语言发育进程里程碑指标中“能够说第1个字的年龄”(X_(1))和“从能够说第1个字到第1个词组之间的时间”(X_(2))作为参数,应用两步聚类法对训练样本的374例孤独症患者进行聚类分析,根据聚类结果建立Bayes判别方程,而后使用该方程对验证样本的310例孤独症患者进行语言发育亚组划分,分析RELN通路上相关基因单核苷酸多态性与各亚组之间的关系。结果:聚类分析将第1部分374例样本分为3类,第1类患者X_(1)为(11.83±4.37)个月,X_(2)为(24.55±8.67)个月;第2类患者X_(1)为(12.17±3.46)个月,X_(2)为(7.07±3.79)个月;第3类患者X_(1)为(30.94±7.60)个月,X_(2)为(4.73±4.80)个月。依据聚类结果建立相应的判别方程:Y_(A)=−14.442+0.525X_(1)+0.810X_(2);Y_(B)=−4.964+0.477X_(1)+0.264X_(2);Y_(C)=−19.843+1.175X_(1)+0.241X_(2)。交叉核实法显示方程误判概率为3.8%。在对验证样本进行亚组划分前,纳入分析的341个单核苷酸多态性位点等位基因频率均未通过校正后的检验水准(P>2.44×10^(−5));而亚组划分后,第2类患者LRP8基因rs1288502位点等位基因频率在病例组与对照组间差异有统计学意义(P=6.45×10^(−6))。结论:通过孤独症患者语言发育情况建立的判别方程在分析RELN信号通路基因与孤独症的关系时有助于降低样本异质性,且RELN信号通路相关基因中LRP8基因与孤独症患者特定类型的语言发育相关。
Objective Autism is a neurodevelopment disorder with unclear etiology.High heterogeneity is one of the main issues in the etiological studies.This study explores the relationship between RELN signaling pathway related genes(RELN,VLDLR,LRP8,DAB1,CDK5,FYN)and language development of autism patients based on a cluster analysis model which is established to reduce the heterogeneity.Methods:Autism children were recruited from 5 different medical/autism training institutes from Hunan,Shandong,and Henan provinces,and were divided into 2 parts according to the recruitment time:The first part was the training sample,which was recruited from October 2006 to May 2011,and the second part was the validation sample,which was recruited from July 2011 to May 2012.A two-step cluster analysis was performed to cluster 374 Chinese Han autism patients into different subgroups based on 2 parameters:Onset age of the first word and interval from the first word to the first phase.A Bayes discriminatory equation was established followed the cluster results.Then we used this equation to divide another 310 autism children into prior defined subgroups.After the genotyping data was screened,a single marker case-control association study was conducted.Results:The cluster analysis clustered 374 samples into 3 subgroups.Onset ages of the first word in the Group A were(11.83±4.37)months and intervals from the first word to the first phase were(24.55±8.67)months;onset ages of the first word in the Group B were(12.17±3.46)months,intervals from the first word to the first phase were(7.07±3.79)months;onset ages of the first word of Group C were(30.94±7.60)months,intervals from the first word to the first phase were(4.73±4.80)months.The established equations based on the cluster analysis were Y_(A)=−14.442+0.525X_(1)+0.810X_(2),Y_(B)=−4.964+0.477X_(1)+0.264X_(2),Y_(C)=−19.843+1.175X_(1)+0.241X_(2).Cross validated analysis showed that the false rate of the equation was 3.8%.A total of 341 single nucleotide polymorphism(SNP)in 6 genes passed the quality control.Before divided subgroups,none of these SNPs reached the significant P value(P>2.44×10^(−5),Bonferroni adjustment).However the result showed that rs1288502 of LRP8 in Group B was significantly different from the control group(P=6.45×10^(−6)).Conclusion:Based on the cluster analysis of language development,we could establish a discriminatory equation to reduce heterogeneity of autism sample.The association test indicates that LRP8 gene in RELN signaling pathway is related to a particular type of language development of autism patients.
作者
沈屹东
董慧茜
赵靖平
夏昆
欧建君
SHEN Yidong;DONG Huixi;ZHAO Jingping;XIA Kun;OU Jianjun(National Clinical Research Center for Mental Disorders,Department of Psychiatry,Second Xiangya Hospital,Central South University,Changsha 410011;Mental Health Center,Xiangya Hospital,Central South University,Changsha 410008;Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics,Central South University,Changsha 410078,China)
出处
《中南大学学报（医学版）》
CAS
CSCD
北大核心
2022年第7期858-864,共7页
Journal of Central South University ：Medical Science
基金
国家重点基础研究发展计划(2012CB517901)
湖南省自然科学基金(2020JJ5830)。
关键词
孤独症
RELN信号通路
聚类分析
判别分析
单核苷酸多态性
autism
RELN signaling pathway
cluster analysis
discrimination analysis
singlenucleotide polymorphism
