Investigating the Systems Genetics of the Patterns of Polysubstance Abuse and Addiction

抽象的。多物质物质使用（PSU）是常见的个人会议 任何物质使用障碍（SUD）的诊断，并定义为使用两个或两个以上 上瘾的毒品这些药物组合与增加的短期和长期 精神和身体健康问题。由于PSU模式的高度可变性， 关于PSU脆弱性的分子机制的数据有限。 该项目的总体目标是使用基于全基因组数据的新方法， 剖析多种物质滥用和成瘾的基本生物学。在R21阶段， 建议，我们将进行遗传力和高分辨率交叉表型多基因风险评分 (PRS)三个中等规模研究人群中PSU类别的概率分析 以高度的PSU为特征，我们的耶鲁-宾夕法尼亚大学队列，SAGE（成瘾研究： 遗传学和环境）队列，以及ICGHD（国际遗传学联盟， 海洛因依赖）队列。PSU模式将通过潜在类别分析进行识别 (LCA)和多项逻辑回归程序的物质使用数据可从 药物依赖和酒精中毒半结构评估 酒精中毒遗传学半结构评估（SSAGA） 组群）和SSAGA-OZ（SSAGA -澳大利亚; ICGHD组群）。我们期望R21期分析将识别可遗传的PSU模式和与它们相关的基因集， 为研究PSU在其他分子模式中的作用提供了必要的背景。在 R33阶段的项目，我们将测试R21阶段的结果，就两个不同的 设置：1）纵向PSU数据;和2）PSU诱导的表观遗传变化。重新接触a 亚样本的耶鲁-宾夕法尼亚大学队列，我们将能够评估的轨迹PSU模式 和PSU的后果，并测试是否与初始的遗传因素有关， PSU状态预测PSU轨迹和后果。同样，我们也将测试 遗传性PSU与表观遗传变化以及这些变化是否介导健康结果相关。 R33阶段的预期结果将提供与以下生物学相关的多项发现： PSU可以改善临床实践，提供新的治疗目标，并开辟新的方向 PSU的分子研究。

Abstract. Polysubstance Substance Use (PSU) is common among individuals meeting diagnosis for any substance use disorder (SUD) and is defined as the use of two or more addictive drugs. These drug combinations are associated with increased short- and long-term mental and physical health concerns. Due to the high degree of variability in PSU patterns, limited data are available regarding the molecular mechanisms underlying PSU vulnerability. The overall goal of this project is to use novel approaches based on genome-wide data to dissect the fundamental biology of polysubstance abuse and addiction. In the R21 phase of this proposal, we will conduct heritability and high-resolution cross-phenotype polygenic risk score (PRS) analyses of probabilities of PSU classes in three moderately-large study populations characterized by a high degree of PSU, our Yale-Penn cohort, the SAGE (Study of Addiction: Genetics and Environment) cohort, and the ICGHD (International Consortium on the Genetics of Heroin Dependence) cohort. The PSU pattern will be identified applying latent class analysis (LCA) and a multinomial logistic regression procedure to substance use data available from the SSADDA (Semi-structured Assessment for Drug Dependence and Alcoholism; Yale-Penn Cohort), the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism; SAGE cohort), and the SSAGA-OZ (SSAGA – Australia; ICGHD cohort). We expect that the R21-Phase analyses will identify heritable PSU patterns and gene sets associated with them, providing the background necessary to investigate PSU in other molecular paradigms. In the R33 phase of the project, we will test the R21-phase results with respect to two different settings: 1) longitudinal PSU data; and 2) PSU-induced epigenetic changes. Re-contacting a sub-sample of the Yale-Penn cohort, we will be able to assess the trajectory of PSU patterns and the consequences of PSU and to test whether the genetic factors associated with the initial PSU status predict the PSU trajectories and consequences. Similarly, we will also test whether heritable PSU correlates with epigenetic changes and whether these mediate health outcomes. The expected results of the R33 phase will provide multiple findings related to the biology of PSU that can improve clinical practice, deliver new therapeutic targets, and open new directions in molecular investigations of PSU.