Substance Abuse & Behavioral Disinhibition: Integrating Genes & Environment

描述（由申请人提供）：我们建议利用对 7300 名父母和双胞胎儿童进行的既定纵向研究来调查基因环境相互作用如何影响药物滥用 (SA) 的发展。我们的重点是对儿童进行反复评估，从 11 岁青春期前开始，然后在大约 14、17、20、24 和 29 岁再次评估，从而可以检查狭义年龄范围内个体差异的发展，这些年龄范围大致对应于与环境背景的重要变化相关的关键生活转变（开始高中、离开父母的家、接触新的同龄人等）。我们的研究涉及具有代表性、高参与率的社区样本，以及全面的、适合年龄的、心理测量学上合理的评估，涵盖 1) 物质使用、滥用和依赖； 2) 与行为抑制解除相关的障碍、人格特质和行为； 3) SA风险的心理生理内表型； 4）来自多个发展阶段的多个领域（家庭关系、创伤、同伴群体质量、接触物质等）的环境逆境。我们建议从大约 5000 名研究参与者那里获取基于血液的 DMA，这些数据连同去识别化的个人数据将被添加到 NIDA 遗传学联盟 (NGC) 公共存储库中。我们将征得另外 2300 名个人参与这项 GEDI 计划的同意，他们的数据已成为 NGC 的一部分。我们将使用 1M SNP 珠阵列与 1000 名父母进行两阶段全基因组关联研究，然后使用三种 SA 相关潜在表型对另外 2700 名父母进行确认基因分型，重点关注 a) SA 风险、b) 行为去抑制属性和 c) 脑电生理学（事件相关电位和振荡）。这三种定量表型将在资助期间的早期开发和完善，以便捕获父母和年轻成年后代中类似的 SA 遗传风险的互补方面。然后，将使用母体研究以及不断发展的 SA 文献中确定的候选基因对后代 (N=3582) 进行基因分型。还将开发环境逆境的综合衡量标准，并将其用于后代 GxE 效应的假设驱动测试，包括检查效应的发育特异性及其在相关措施、发育时间点和后代样本中的可复制性。还包括假设生成的探索性分析，这些分析利用了我们家族提供的丰富的表型数据以及分子生物学和统计遗传学的快速发展。

DESCRIPTION (provided by applicant): We propose using established longitudinal studies of 7300 parents and twin children to investigate how gene environment interplay influences the development of substance abuse (SA). Our focus is on children assessed repeatedly, beginning in pre-adolescence at age 11 and then again at approximately ages 14, 17, 20, 24, and 29, making it possible to examine the development of individual differences within narrowly defined age ranges that correspond roughly to key life transitions associated with important changes in environmental context (starting high school, leaving the parental home, exposure to new peers, etc). Our studies involve representative, community based samples with high participation rates, and thorough age appropriate, psychometrically sound assessments covering 1) substance use, misuse, and dependence; 2) disorders, personality traits, and behaviors related to behavioral disinhibition; 3) psychophysiogical endophenotypes for SA risk; and 4) environmental adversity derived from multiple domains (family relationships, trauma, peer group quality, exposure to substances, etc.) over multiple developmental stages. We propose obtaining blood-based DMA from approximately 5000 study participants which, along with deidentified personal data, will be added to the NIDA Genetics Consortium (NGC) public repository. We will obtain consent to participate in this GEDI initiative from an additional 2300 individuals whose data will already be part of the NGC. We will carry out a 2-stage genome wide association study using a 1M SNP bead array with 1000 parents followed by confirmation genotyping with an additional 2700 parents using three SA related latent phenotypes focused on a) SA risk, b) behavioral disinhibition attributes, and c) brain electrophysiology (event related potentials and oscillations). These three quantitative phenotypes will be developed and refined early in the funding period so as to capture complementary aspects of genetic risk for SA similarly in parents and young adult offspring. Offspring (N=3582) will then be genotyped using candidate genes identified in the parent study as well as in the evolving SA literature. A composite measure of environmental adversity will also be developed and used in hypothesis driven tests of GxE effects in offspring that include examination of the developmental specificity of effects and their replicability across related measures, developmental time points, and offspring samples. Also included will be hypothesis-generating exploratory analyses that take advantage of the richness of the phenotypic data available from our families and the rapid pace of development in molecular biology and statistical genetics.