Genetics of Adolescent Antisocial Drug Dependence

描述(由申请人提供)：本申请继续根据发展议程012845发起的多地点合作，以解决青少年发病的反社会药物依赖的遗传流行病学中的关键问题。解决这些问题需要超过单个站点合理获得的样本量，以及精神病学家、心理学家以及行为和分子遗传学家的多学科专业知识，这在单个站点很难提供。这种合作包括对先前研究的先证者和兄弟姐妹进行纵向评估，并增加了社区控制。它将产生总共约800名临床先证者，连同他们的兄弟姐妹，以评估不同的发展轨迹和临床进程，以及共病、早发和家族负荷的作用。在允许停药后，我们预计将有大约600例持续性病例及其兄弟姐妹的最终样本，以及大约600名对照受试者的匹配样本，用于持续性、青春期发病、反社会物质依赖的遗传关联分析。目前的应用将使用密集的SNP关联图谱来识别易患这种行为模式的遗传基因座。该项目的具体目标如下：1)我们将完成对年龄在19岁到23岁之间的约800名临床先证者及其兄弟姐妹的5年随访评估，并从我们现有的数据库中确定匹配的对照对象样本，以及300名新确定的对照对象。新的评估将在圣地亚哥和丹佛进行。2)我们将评估不同的发育轨迹和临床病程，以及合并症、早发和家族负担在这些方面的作用。我们正在收集的数据集，即使在没有单一的DMA样本的情况下，也将代表着一个独特的、无与伦比的研究资源，用于研究青少年反社会药物依赖的发展和家庭影响。3)我们将使用Affymetrix SNP芯片技术对200个药物依赖易感性和/或品行障碍候选基因中的每个基因平均25个SNP进行基因分型。4)我们将使用-600个持续病例及其~600个匹配对照进行关联分析，然后使用家庭内关联分析对最佳信号进行验证性检验(Laird和Lange，2006)。这些分析将证实遗传与青春期持续的反社会药物依赖的相关性的重要性和稳健性。5)通过继续我们的NIDA遗传学联盟数据共享协议，我们将共享所有核心物质依赖和精神病理学表型数据，以及为多点样本建立的淋巴母细胞系的DNA。我们的Affymetrix SNP芯片将以成本价提供给任何合格的研究人员。

DESCRIPTION (provided by applicant): This application continues a multisite collaboration, initiated under DA 012845, to address critical issues in the genetic epidemiology of adolescent onset antisocial drug dependence. Addressing these issues requires sample sizes greater than a single site can reasonably attain, as well as the multidisciplinary expertise of psychiatrists, psychologists, and behavioral and molecular geneticists, that is difficult to provide at a single site. This collaboration includes longitudinal assessment of previously studied probands and siblings, and adds community controls. It will yield a total of ~800 clinical probands, together with their siblings, to assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading. After allowing for desistance, we anticipate a final sample of ~600 persistent cases, together with their siblings, and a matched sample of ~600 control subjects, for genetic association analyses of persistent, adolescent onset, antisocial substance dependence. The current application will use dense SNP association mapping to identify genetic loci predisposing to this pattern of behavior. The specific aims of the project are as follows: 1) We will complete the five year follow-up assessment of ~800 clinical probands, aged 19 though 23 years at follow-up, and their siblings, and ascertain a sample of matched control subjects from our existing databases together with 300 newly ascertained control subjects. The new assessments will be conducted at the San Diego and Denver sites. 2) We will assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading on these. The data set we are collecting would, even in the absence of a single DMA sample, represent a unique, and unsurpassed, research resource for studying the development and familial influences on adolescent antisocial drug dependence. 3) We will use Affymetrix SNP chip technology to genotype an average of 25 SNPs in each of 200 candidate genes for drug dependence vulnerability and/or conduct disorder. 4) We will conduct association analyses using the -600 persistent cases and their ~600 matched controls, and then conduct confirmatory tests of the best signals using a within-family association analysis (Laird and Lange, 2006). These analyses will confirm the significance and robustness of genetic associations with adolescent onset persistent antisocial drug dependence. 5) Through a continuation of our NIDA Genetics Consortium data sharing agreement, we will share all the core substance dependence and psychopathology phenotypic data, and DNA from lymphoblastoid cell lines established for the multisite samples. Our Affymetrix SNP chip will be made available, at cost, to any qualified researcher.