Substance Abuse & Behavioral Disinhibition: Integrating Genes & Environment

描述（由申请人提供）：我们建议使用7300名父母和双胞胎儿童的纵向研究，以调查基因环境的相互作用如何影响药物滥用（SA）的发展。我们的重点是反复评估的儿童，从11岁的青春期前开始，然后在大约14岁，17岁，20岁，24岁和29岁时再次进行评估，从而有可能在狭窄的年龄范围内检查个体差异的发展，这些年龄范围大致对应于与环境背景中的重要变化相关的关键生活转变（开始上高中，离开父母家，接触新的同龄人等）。我们的研究涉及具有代表性的、以社区为基础的样本，参与率高，并进行了全面的年龄适当的、心理测量学上合理的评估，包括1）物质使用、滥用和依赖; 2）与行为去抑制相关的障碍、人格特质和行为; 3）SA风险的心理生理学内表型;（4）来自多个领域（家庭关系、创伤、同伴群体素质、接触物质等）的环境逆境在多个发展阶段。我们建议从大约5000名研究参与者中获得基于血液的DMA，这些参与者沿着去识别的个人数据将被添加到NIDA遗传学联盟（NGC）公共存储库中。我们将获得另外2300名个人的同意，他们的数据已经是NGC的一部分。我们将使用1 M SNP微珠阵列对1000个亲本进行2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个亲本进行确认基因分型，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早期开发和完善，以便在父母和年轻成年后代中类似地捕获SA遗传风险的互补方面。然后使用母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。环境逆境的综合措施也将被开发和使用在假设驱动的测试GxE的影响，包括检查的发展特异性的影响和它们的可复制性在相关的措施，发展的时间点，和后代样本的后代。还将包括假设生成的探索性分析，利用丰富的表型数据，从我们的家庭和快速发展的分子生物学和统计遗传学。

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.