Project 4 - Human studies to identify genes and characterize risk pathways involved in alcohol related outcomes

项目摘要-项目4 VCU酒精研究中心的项目4将利用人类数据来实现两个互补的目标： (1)使用新的多变量基因组学方法， 技术，以及（2）表征与不同纵向样本中识别的变体相关的风险， 为了了解整个发育过程中与已鉴定变体相关的表型谱， 与环境结合。这些领域中的每一个都代表了利用遗传数据 改善酒精使用障碍（AUDs）的预防、干预和治疗，并将为 我们进入了个性化医疗的时代。酒精使用障碍的人类基因鉴定工作滞后 落后于其他精神病学领域，部分原因是可用AUD病例的样本量有限。然而，在这方面， 最近对消费和澳元的荟萃分析显示，与许多其他因素存在显着的遗传相关性。 精神和行为特征，以及社会和人口统计结果，以及其他生物医学 表型项目4将（目标1）应用新的多元遗传方法来利用遗传共享 酒精使用表型与其他精神和行为特征之间的关系，以提高检测能力 与酒精使用结果相关的常见变异，并描述潜在的途径， 遗传变异的作用。这些鉴定的遗传变体结果的生物信息学表征通过 生物信息学和分析（BIA）核心将有助于阐明潜在的生物风险途径。然后我们将 将这些多变量分析的结果应用于三个互补的纵向数据集， 基于人群和高风险样本，以便（目标2a）：绘制与以下相关的行为表型： 在目标1中确定的青春期和成年初显期的遗传风险评分;（目标2b）测试 特定于性别和种族/族裔背景的风险途径;以及（目标2c）检测遗传风险的适度性 关键的环境因素。该项目将以多种方式与其他ARC组件连接： 基因发现分析的结果（目标1）将与模式生物结果相结合， 在BAI核心中的表达数据（项目1-3），以创建精细的多基因风险评分，用于目标2中的进一步研究。 项目5将使用双胞胎和流行病学样本完善结构模型， 遗传对酒精相关结果的影响的多变量性质，以迭代地告知和扩展 在目标1中进行多变量分析。此外，目标1中鉴定的遗传变体可用于 通过啮齿动物行为核心在动物模型中进行进一步研究。

Project Summary – Project 4 Project 4 of the VCU Alcohol Research Center will utilize human data to accomplish two complementary goals: (1) advancing discovery of genes involved in alcohol-related outcomes using new multivariate genomic techniques, and (2) characterizing the risk associated with identified variants in diverse longitudinal samples, in order to understand the spectrum of phenotypes associated with identified variants, across development, and in conjunction with the environment. Each of these areas represent critical steps in using genetic data to improve prevention, intervention, and treatment for alcohol use disorders (AUDs), and will lay the foundation as we move into an era of personalized medicine. Human gene identification efforts for alcohol use disorders lag behind other areas of psychiatry, in part due to constrained sample sizes of available AUD cases. However, recent meta-analyses of consumption and AUD reveal significant genetic correlations with numerous other psychiatric and behavioral traits, as well as social and demographic outcomes, and other biomedical phenotypes. Project 4 will (Aim 1) apply new multivariate genetic methods to capitalize on genetic sharing between alcohol use phenotypes and other psychiatric and behavioral traits in order to boost power to detect common variants associated with alcohol use outcomes, and to characterize the latent pathways by which genetic variants operate. Bioinformatic characterization of these identified genetic variant results through the Bioinformatics and Analytics (BIA) core will help elucidate underlying biological risk pathways. We will then apply results from these multivariate analyses to three complementary longitudinal datasets, consisting of both population-based and high-risk samples, in order to (Aim 2a): map the behavioral phenotypes associated with the genetic risk scores identified in Aim 1 across adolescence and emerging adulthood; (Aim 2b) test for pathways of risk specific to sex and racial/ethnic background; and (Aim 2c) test for moderation of genetic risk by key environmental factors. The project will interface with the other ARC components in multiple ways: results from the gene discovery analyses (Aim 1) will be integrated with model organism results and expression data (Projects 1-3) in the BAI Core to create refined polygenic risk scores for further study in Aim 2. Project 5 will refine structural models using twin and epidemiological samples to further characterize the multivariate nature of genetic influences on alcohol-related outcomes, to iteratively inform and extend the multivariate analyses performed in Aim 1. Further, the genetic variants identified in Aim 1 can be advanced for further study in animal models via the Rodent Behavior Core.