Gene-Environment Interplay in the Development of Drug Abuse, HIV Sexual Risk Beha

这一拟议的R 01由三项正在进行的纵向研究组成：西雅图社会研究 开发项目（SSDP，Karl G.希尔，PI），提高健康儿童项目（RHC，理查德F。卡塔拉诺， PI）和明尼苏达州双胞胎和家庭研究中心（MCTFR，Matthew McGue， William Iacono，PI）。为拟议的研究奠定基础，工作将在目前两年内完成。 ARRA赠款允许SSDP（1）创建成瘾表型的测量和成瘾表型的测量。 适合于基因-环境分析的环境;（2）环境和表型的测试模型 适合以后纳入遗传数据，（3）从SSDP纵向面板收集DNA样本，以及（4） 进行全基因组基因分型，以预期随后的遗传关联和G-E分析。的 拟议的R 01将通过进行遗传关联分析和检查G-E相互作用来扩展这项工作， 成瘾和艾滋病毒性风险行为的发展，不受ARRA资助的任务。目标1 我们将利用来自SSDP、RHC、MCTFR的数据以及来自基因型和表型的三个样本 （dbGaP）存档，以开发与成瘾相关的三个系统的遗传系统脆弱性评分： 多巴胺血清素和GABA目标1还审查了这些遗传系统脆弱性的贡献 得分与HIV危险性行为、吸毒和犯罪有关。目标2将研究遗传机制 通过测试和重复对成瘾影响以及基因-环境相关性和交互作用 策略采用SSDP，RHC和MCTFR样本。Aim 2还检查了这些基因环境在多大程度上 模型预测艾滋病毒风险性行为，非法药物使用和犯罪。目标3将检查基因x 干预相互作用（GxI），以及遗传因素对问题结果的影响是否可以 在儿童时期通过社会发展预防干预减轻。这项研究建立在数据基础上。 现有的可比表型，个人和环境的措施，在三个良好的特点， 纵向样本其中两个数据集（SSDP和MCTFR）已经有了全基因组基因型数据， RHC已经收集了DNA准备进行基因分型所有三个小组都包含环境指标， 从童年到成年，多次评估烟草和酒精使用以及问题使用的风险因素。 所有三个面板还包括DSM-IV诊断评估以及其他药物定量测量。 滥用和依赖以及已证实的遗传性的相关表型。最后，SSDP和RHC 对父母、教师和儿童进行社会发展预防干预， 允许检测基因X干预相互作用。SSDP、RHC和MCTFR的联盟 研究小组提供了一个机会，了解如何，在不同的发展阶段，环境因素， 可能会放大或减少烟草和酒精问题的遗传脆弱性。调查结果将为设计提供信息 改善对这些常见且昂贵的疾病的预防和治疗干预措施。

This proposed R01 constitutes a collaboration among three ongoing longitudinal studies: the Seattle Social Development Project (SSDP, Karl G. Hill, PI), the Raising Healthy Children Project (RHC, Richard F. Catalano, PI) and projects from the Minnesota Center for Twin and Family Research (MCTFR, Matthew McGue, and William Iacono, PIs). To lay the foundation for the proposed study, work to be completed under the current twoyear ARRA grant has permitted SSDP to (1) create measures of addiction phenotypes and measures of the environment suitable for gene-environment (G-E) analysis, (2) test models of environment and phenotype suitable for later inclusion of genetic data, (3) collect DNA samples from the SSDP longitudinal panel and (4) conduct a whole-genome genotyping in anticipation of subsequent genetic association and G-E analyses. The proposed R01 will extend this work by conducting genetic association analyses and examining G-E interplay in the development of addiction and HIV sexual risk behavior, tasks not supported by the ARRA grant. In Aim 1 we will utilize data from SSDP, RHC, MCTFR and three samples from the Genotypes and Phenotypes (dbGaP) archive to develop genetic system vulnerability scores for three systems related to addiction: dopamine, serotonin and GABA. Aim 1 also examines the contribution of these genetic system vulnerability scores to HIV sexual risk behavior, illicit drug use and crime. Aim 2 will examine mechanisms of genetic influence on addiction as well as gene-environment correlation and interaction through a test-and-replicate strategy employing SSDP, RHC and MCTFR samples. Aim 2 also examines the extent to which these geneenvironment models predict HIV-sexual risk behavior, illicit drug use and crime. Aim 3 will examine gene x intervention interaction (GxI), and whether the influence of genetic factors on problem outcomes can be mitigated by social developmental preventive intervention during childhood. The proposed study builds on data sets of existing comparable phenotypic, individual and environmental measures in three well-characterized, longitudinal samples. Two of the data sets (SSDP and MCTFR) already have whole-genome genotypic data, and RHC has DNA collected and ready to be genotyped. All three panels contain indicators of environmental risk factors for tobacco and alcohol use and problem use assessed multiple times from childhood to adulthood. All three panels also include assessments of DSM-IV diagnoses as well as other quantitative measures of drug abuse and dependence and related phenotypes of demonstrated heritability. Finally, both SSDP and RHC implemented a social-developmental preventive intervention with parents, teachers and children early in life, permitting examination of gene x intervention interaction. The alliance of the SSDP, RHC and MCTFR research teams provides an opportunity to learn how, at different developmental periods, environmental factors might amplify or reduce genetic vulnerability to tobacco and alcohol problems. Findings will inform the design of improved preventive and treatment interventions for these common and costly disorders.