Using dimensional models of externalizing psychopathology to aid in gene identification
Using dimensional models of externalizing psychopathology to aid in gene identification
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DOI：
10.1001/archpsyc.65.3.310
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发表时间：
2008-03-01
影响因子：
--
通讯作者：
Goate, Alison
中科院分区：
文献类型：
--
作者：
Dick, Danielle M.;Aliev, Fazil;Goate, Alison
背景：双胞胎研究提供了令人信服的证据，表明酒精和药物依赖、儿童行为障碍、成人反社会行为和去抑制性人格特征具有共同的潜在遗传责任，导致一系列外化行为。然而，这些信息还没有被广泛应用于基因鉴定工作中，这些努力主要集中在使用传统精神病学分类系统诊断的特定疾病上。目的：测试在(1)连锁分析和(2)关联分析中使用多变量外化表型来识别与外在疾病谱广泛相关的基因的实用性。设计：数据来自酒精中毒遗传学合作研究。使用来自全基因组10 cM微卫星扫描的数据进行连锁分析。对候选基因--M胆碱型乙酰胆碱受体M2基因(CHRM2)的27个单核苷酸多态进行了关联分析。地点：美国6个中心。其他参与者：来自262个家庭的约2300人。主要观察指标：酒精依赖、非法药物依赖、儿童品行障碍、成人反社会人格障碍的终生症状计数以及由前6个变量组成的新奇寻求、感觉寻求和一般外化成分得分。结果：主成分分析表明，6个个体变量加载到单个外化因素上。使用合成成分分数的连锁分析确定了7号染色体上的一个区域，该区域与一个基因一致，该基因广泛地倾向于个体的外化行为。对候选基因CHRM2的关联分析表明，它与一般的外化表型有关。结论：对精神障碍的更广泛的概念化，如研究一系列外化精神病理学，可能有助于识别易感基因，并了解遗传因素影响各种不良结局易感性的途径。
Context: Twin studies provide compelling evidence that alcohol and drug dependence, childhood conduct disorder, adult antisocial behavior, and disinhibitory personality traits share an underlying genetic liability that contributes to a spectrum of externalizing behaviors. However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems.Objective: To test the utility of using a multivariate externalizing phenotype in ( 1) linkage analyses and ( 2) association analyses to identify genes that contribute broadly to a spectrum of externalizing disorders.Design: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism. Linkage analyses were conducted using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 single-nucleotide polymorphisms genotyped across a candidate gene, the muscarinic acetylcholine receptor M2 gene ( CHRM2).Setting: Six centers across the United States.Other Participants: Approximately 2300 individuals from 262 families.Main Outcome Measures: Lifetime symptom counts of alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder and novelty seeking, sensation seeking, and general externalizing component scores consisting of a composite of the previous 6 variables.Results: Principal component analyses indicated that the 6 individual variables loaded on a single externalizing factor. Linkage analyses using the resultant component scores identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of a candidate gene, CHRM2, previously of interest in the Collaborative Study on the Genetics of Alcoholism, suggest that it is involved in a general externalizing phenotype.Conclusions: Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.