Genetics of Adolescent Antisocial Drug Dependence

青少年反社会药物依赖的遗传学

• 批准号: 7999209
• 负责人: SANDRA A BROWN
• 金额: $ 41.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999209
• 关键词: Address; Adolescence; Adolescent; Affect; Agreement; Behavior; Behavioral; Candidate Disease Gene; Clinical; Collaborations; Communities; Comorbidity; Conduct Disorder; DNA; Data; Data Set; Databases; Development; Drug Addiction; Drug abuse; Elements; Family; Genetic; Genotype; Guidelines; Health; Individual; Maps; Molecular; National Institute of Drug Abuse; Neurobiology; Pattern; Phenotype; Plant Roots; Psychiatrist; Psychologist; Psychopathology; Qualifying; Research Personnel; Resources; Role; Sample Size; Sampling; Siblings; Signal Transduction; Site; Substance Addiction; Susceptibility Gene; Technology; Testing; aged; anti social; cost; data sharing; early onset; follow up assessment; follow-up; genetic association; genetic epidemiology; lymphoblastoid cell line; multidisciplinary; proband

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.

描述（由申请人提供）：本申请继续在DA 012845下启动的多站点合作，以解决青少年发病反社会药物依赖的遗传流行病学中的关键问题。解决这些问题需要比单个站点更大的样本量，以及精神病学家、心理学家、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。这项合作包括对先前研究的先证者和兄弟姐妹进行纵向评估，并增加社区控制。它将产生总计约800个临床先证者，连同他们的兄弟姐妹，以评估不同的发育轨迹和临床病程，以及合并症、早期发病和家族负荷的作用。在考虑到阻力后，我们预计将有大约600例持续病例的最终样本，连同他们的兄弟姐妹，以及大约600名对照受试者的匹配样本，用于持续的，青春期发病的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关联映射来识别易导致这种行为模式的遗传位点。该项目的具体目的如下：1)我们将完成对约800名临床先证者（随访时年龄在19 - 23岁之间）及其兄弟姐妹进行为期5年的随访评估，并从我们现有的数据库中确定匹配的对照受试者样本，以及300名新确定的对照受试者。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过程，以及合并症、早期发病和家族负荷在这些方面的作用。我们正在收集的数据集，即使没有单一的DMA样本，也将代表一个独特的，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/或行为障碍候选基因进行平均25个SNP的基因分型。4)我们将使用-600例持续病例及其-600例匹配对照进行关联分析，然后使用家族内关联分析对最佳信号进行验证性测试（Laird和Lange， 2006）。这些分析将证实遗传关联与青少年发病持续反社会药物依赖的重要性和稳健性。5)通过我们NIDA遗传学联盟数据共享协议的延续，我们将共享所有核心物质依赖和精神病理表型数据，以及为多位点样本建立的淋巴母细胞样细胞系的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。