Substance Abuse & Behavioral Disinhibition: Integrating Genes & Environment

描述（由申请人提供）：我们建议使用已建立的7300对父母和双胞胎子女的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。我们的重点是反复评估儿童，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的重要变化相关的关键生活转变（开始高中生活，离开父母家，接触新的同龄人等）。我们的研究包括具有代表性的、以社区为基础的高参与率的样本，以及全面的、适合年龄的、心理测量学上健全的评估，包括1)物质使用、滥用和依赖；2)与行为去抑制相关的障碍、人格特征和行为；3) SA风险的心理生理内表型；4)来自多个发展阶段的多领域（家庭关系、创伤、同伴群体质量、物质暴露等）的环境逆境。我们建议从大约5000名研究参与者中获得基于血液的DMA，这些数据将与未识别的个人数据一起添加到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，他们的数据将成为NGC的一部分。我们将使用1M SNP头阵列对1000名父母进行两阶段的全基因组关联研究，然后对另外2700名父母进行基因分型确认，使用三种与SA相关的潜在表型，重点是a) SA风险，b)行为去抑制属性和c)脑电生理（事件相关电位和振荡）。这三种定量表型将在资助期早期发展和完善，以便在父母和年轻成年后代中捕捉SA遗传风险的互补方面。后代（N=3582）将使用在亲本研究中鉴定的候选基因以及在不断发展的SA文献中鉴定的候选基因进行基因分型。还将开发一种环境逆境的综合测量方法，并将其用于GxE对后代影响的假设驱动测试，包括检查影响的发育特异性及其在相关测量方法、发育时间点和后代样本之间的可重复性。还将包括假设生成的探索性分析，利用从我们的家庭中获得的丰富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.