个体基因组与先兆子痫的交互作用对孤独症谱系障碍症状严重程度的影响  

Impact of interaction between individual genomes and preeclampsia on the severity of autism spectrum disorder symptoms

作　　者：王晓萌 吴代 罗腾飞 范伟女[1] 李津臣 WANG Xiaomeng;WU Dai;LUO Tengfei;FAN Weinü;LI Jinchen(Department of Neurology,Ningbo No.2 Hospital,Ningbo Zhejiang 315010;Guoke Ningbo Life Science andHealth Industry Research Institute,Ningbo Zhejiang 315000;Hunan Key Laboratory of Medical Genetics,School of Life Sciences,Central South University,Changsha 410008;National Clinical Research Center forGeriatric Disorders,Xiangya Hospital,Central South University,Changsha 410008;Bioinformatics Center,Xiangya Hospital,Central South University,Changsha 410008,China)

机构地区：[1]宁波市第二医院神经内科,浙江宁波315010 [2]国科宁波生命与健康产业研究院,浙江宁波315000 [3]中南大学生命科学学院医学遗传学湖南省重点实验室,长沙410008 [4]国家老年疾病临床医学研究中心(湘雅医院),长沙410008 [5]中南大学湘雅医院生物信息中心,长沙410008

出　　处：《中南大学学报（医学版）》2024年第8期1187-1199,共13页Journal of Central South University ：Medical Science

基　　金：国家自然科学基金(32070591);湖湘青年英才(2021RC3060);第四轮宁波市医学重点学科建设计划(2022-B12)。

摘　　要：目的:孤独症谱系障碍(autism spectrum disorder,ASD)是一种复杂的神经发育障碍。既往研究表明,遗传易感性和环境暴露,如母亲妊娠期先兆子痫(preeclampsia,PE),在ASD的病理机制中扮演重要角色。然而,遗传因素和环境因素的相互作用对于ASD表型严重程度的具体影响尚不明确。本研究通过构建基因-环境模型,旨在探讨个体基因组中的新发变异(de novo variants,DNVs)和常见变异与母亲妊娠期PE暴露的交互作用对ASD表型严重程度的影响。方法:从西蒙斯孤独症收集项目(Simons Simplex Collection,SSC)数据库中提取4~18岁的单纯特发性ASD患者的表型数据。根据ASD患者的生物学母亲是否患有PE(即患者是否PE暴露),将研究对象分为PE^(+)组和PE^(-)组;将未携带DNVs的研究对象分为DNV^(−)PE^(+)组和DNV^(−)PE^(−)组,将携带DNVs的研究对象分为DNV^(+)PE^(+)组和DNV^(+)PE^(-)组;将多基因风险评分(polygenic risk score,PRS)低于其中位数的研究对象分为PRS^(low)PE^(+)组和PRS^(low)PE^(−)组,将PRS高于或等于其中位数的研究对象分为PRS^(high)PE^(+)组和PRS^(high)PE^(-)组。ASD的核心表型评估包括适应和认知能力、社交互惠能力、语言和交流能力、刻板行为。适应和认知能力评分包括文兰适应行为量表第2版(Vineland Adaptive Behavior Scales,Second Edition,VABS-II)中自适应行为的综合评分、SSC数据库中评定的言语智商(verbal intelligence quotient,VIQ)、SSC数据库中评定的非言语智商(nonverbal intelligence quotient,NVIQ)。社交互惠能力评分包括孤独症诊断访谈量表-修订版(Autism Diagnostic Interview-Revised,ADI-R)中社会维度(ADI-R social domain,ADI-R SD)评分、孤独症诊断观察表(Autism Diagnostic Observation Schedule,ADOS)中社会情感维度(ADOS social affective domain,ADOS SA)评分、社交反应量表(Social Responsiveness Scale,SRS)的正态性分布评分。语言和交流能力评分包括ADI-R中言语交流维度(ADObjective:Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder.Prior research suggests that genetic susceptibility and environmental exposures,such as maternal preeclampsia(PE)during pregnancy,play key roles in ASD pathogenesis.However,the specific effects of the interaction between genetic and environmental factors on ASD phenotype severity remain unclear.This study aims to investigate how interactions between de novo variants(DNVs)and common variants in individual genomes and PE exposure affect ASD symptom severity by constructing a gene-environment model.Methods:Phenotypic data were obtained from the Simons Simplex Collection(SSC)database for idiopathic ASD patients aged 4−18.Subjects were divided based on maternal PE status:PE^(+)(exposed)and PE^(−)(unexposed)groups.Those without DNVs were divided into DNV^(−)PE^(+) and DNV^(−)PE^(−) groups,and those with DNVs into DNV^(+)PE^(+) and DNV^(+)PE^(−) groups.Based on polygenic risk scores(PRS),subjects below the median were classified into PRS^(low)PE^(+)and PRS^(low)PE^(−)groups,and those at or above the median into PRS^(high)PE^(+)and PRS^(high)PE^(−)groups.Core ASD phenotypic assessed included adaptive and cognitive abilities,social reciprocity,language and communication skills,and repetitive behaviors.Adaptive and cognitive abilities were scored using adaptive behavior composite scores from the Vineland Adaptive Behavior Scales,Second Edition(VABS-II),along with verbal intelligence quotient(VIQ)and nonverbal intelligence quotient(NVIQ)scores from the SSC database.Social reciprocity abilities were measured using the social domain scores from the Autism Diagnostic Interview-Revised(ADI-R SD),social affective domain scores from the Autism Diagnostic Observation Schedule(ADOS SA),and normalized scores from the Social Responsiveness Scale(SRS).Language and communication abilities were assessed through verbal communication domain(ADI-R VC),nonverbal communication domain(ADI-R NVC)scores from ADI-R,and the communication and social dom

关 键 词：基因-环境模型 交互作用 孤独症谱系障碍 表型 先兆子痫 新发变异 常见变异 

分 类 号：R749.94[医药卫生—神经病学与精神病学]