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

抽象的。多物质使用(PSU)在符合以下条件的个人中很常见 诊断为任何物质使用障碍(SUD)，定义为使用两种或两种以上 令人上瘾的毒品。这些药物组合与短期和长期的增加有关。 心理和身体健康方面的问题。由于PSU图案的高度可变性， 关于PSU漏洞背后的分子机制，可用的数据有限。 这个项目的总体目标是使用基于全基因组数据的新方法来 剖析多物质滥用和成瘾的基本生物学。在此的R21阶段 建议，我们将进行遗传性和高分辨率的交叉表型多基因风险评分 三个中等规模研究群体中PSU类的概率(PRS)分析 以高度PSU为特征，我们耶鲁-宾夕法尼亚大学的队列，SAGE(成瘾研究： 遗传学和环境)队列，以及国际遗传和环境研究联合会(ICGHD) 海洛因依赖)队列。将使用潜在类分析来识别PSU模式 (LCA)和多项逻辑回归程序，以获得物质使用数据 药物依赖和酒精中毒半结构评估 队列)，SSAGA(酒精中毒遗传学半结构评估；SAGE SSAGA-OZ(SSAGA-澳大利亚；日内瓦排雷中心队列)。我们预计R21阶段的分析将确定可遗传的PSU模式和与其相关的基因集， 为在其他分子范例中研究PSU提供了必要的背景。在 R33阶段的项目，我们将测试R21阶段关于两个不同阶段的结果 设置：1)纵向PSU数据；2)PSU诱导的表观遗传学变化。正在重新联系A 耶鲁-宾夕法尼亚队列的子样本，我们将能够评估PSU模式的轨迹 以及PSU的后果，并测试遗传因素是否与初始 PSU状态预测PSU的轨迹和后果。同样，我们也将测试 可遗传的PSU与表观遗传学变化相关，以及这些变化是否调节了健康结果。 R33阶段的预期结果将提供与生物学有关的多个发现 PSU可以改善临床实践，提供新的治疗靶点，并开辟新的方向 在PSU的分子研究中。

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.