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

建议的R01构成了正在进行的三项纵向研究之间的合作：西雅图社会 发展项目(SSDP，Karl G.Hill，PI)，养育健康儿童项目(RHC，Richard F.Catalano， PI)和明尼苏达州双胞胎和家庭研究中心(MCTFR、Matthew McGue和 William Iacono，PI)。为拟议的研究奠定基础，目前两年内将完成的工作 ARRA赠款允许SSDP(1)创建成瘾表型的测量和 适合基因-环境(G-E)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纵向板收集DNA样本和(4) 进行全基因组基因分型，以预测随后的遗传关联和G-E分析。这个 建议的R01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HIV性危险行为的发展，这些任务没有得到ARRA赠款的支持。在目标1中 我们将利用SSDP、RHC、MCTFR以及三个来自基因和表型的样本 (DBGaP)档案，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、5-羟色胺和GABA。目标1还检查了这些遗传系统脆弱性的贡献 与艾滋病毒性行为、非法药物使用和犯罪有关的分数。目标2将研究遗传基因的机制 通过测试和复制对成瘾以及基因-环境相关性和交互作用的影响 采用SSDP、RHC和MCTFR样本的策略。目标2还检查了这些遗传环境在多大程度上 模型预测了艾滋病毒-性行为、非法药物使用和犯罪。目标3将检查基因x 干预交互作用(GXI)，以及遗传因素对问题结果的影响是否可以 通过儿童时期的社会发展预防性干预来缓解。拟议的研究建立在数据的基础上 现有的三套可比表型、个体和环境措施， 纵向样品。其中两个数据集(SSDP和MCTFR)已经具有全基因组基因数据， RHC已经收集了DNA，并准备进行基因分型。所有三个面板都包含环境指标 烟酒使用和问题使用的风险因素从童年到成年进行了多次评估。 所有三个小组还包括对DSM-IV诊断的评估以及对药物的其他定量测量 虐待和依赖以及相关的遗传性表型。最后，SSDP和RHC 在儿童早期对父母、教师和儿童实施了社会发展预防性干预， 允许对基因x干预交互作用进行检验。社会民主党、RHC和MCTFR的联盟 研究团队提供了一个机会，了解在不同的发展时期，环境因素是如何 可能放大或降低对烟草和酒精问题的遗传易感性。调查结果将为设计提供依据 改善对这些常见和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.