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

研究多物质滥用和成瘾模式的系统遗传学

• 批准号: 10368162
• 负责人: RENATO POLIMANTI
• 金额: $ 65.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368162
• 关键词: Affect; Alcoholism; Alcohols; Algorithms; Attention deficit hyperactivity disorder; Australia; Behavioral; Biology; Bipolar Disorder; Cannabis; Childhood; Cocaine; Cohort Studies; Data; Diagnosis; Drug Addiction; Drug Combinations; Environment; Epigenetic Process; Evaluation; Genes; Genetic; Genetic Variation; Goals; Health; Heritability; Heroin Dependence; Individual; Intelligence; International; Investigation; Link; Logistic Regressions; Major Depressive Disorder; Mediating; Mental Health; Mental disorders; Methods; Methylation; Modeling; Modification; Molecular; Neurotic Disorders; Nicotine; Opioid; Outcome; Pathway interactions; Pattern; Personal Satisfaction; Personality; Pharmaceutical Preparations; Phase; Phenotype; Post-Traumatic Stress Disorders; Probability; Procedures; Prognosis; Resolution; Risk; Sampling; Schizophrenia; Schools; Social Sciences; Statistical Methods; Structure; Substance Use Disorder; Substance abuse problem; System; Testing; Translating; addiction; autism spectrum disorder; base; clinical practice; cohort; college; depressive symptoms; epigenome; experience; follow-up; genetic association; genetics of alcoholism; genome wide association study; genome-wide; genome-wide analysis; improved; insight; meetings; neuroimaging; new therapeutic target; novel strategies; physical conditioning; polygenic risk score; polysubstance abuse; polysubstance use; prospective; psychiatric genomics; public health relevance; risk variant; statistics; study population; substance use; trait

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.

抽象的。在会议的个体中，Polysubstance用途（PSU）很常见 任何药物使用障碍（SUD）的诊断，定义为使用两个或更多 加性药物。这些药物组合与短期和长期增加有关 身心健康问题。由于PSU模式的差异很高， 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来 剖析滥用和成瘾的基本生物学。在R21阶段 提案，我们将进行遗传力和高分辨率跨表型多基因风险评分 （PRS）在三个中等大型研究人群中对PSU类可能性的分析 我们的耶鲁大学耶鲁大学队列的高度PSU的特征是圣人（成瘾研究： 遗传学和环境）和ICGHD（国际关于遗传学国际联盟 海洛因依赖）队列。 PSU模式将被确定应用潜在类别分析 （LCA）和用于物质使用数据的多项式逻辑回归程序可从 SSADDA（对药物依赖和酒精中毒的半结构化评估；耶鲁·佩恩 同类），SSAGA（对酒精中毒遗传学的半结构化评估； Sage 队列）和Ssaga-oz（SSAGA - 澳大利亚； ICGHD队列）。我们预计R21相分析将确定可遗传的PSU模式和与之相关的基因集， 提供在其他分子范式中研究PSU所需的背景。在 R33阶段的项目，我们将相对于两个不同的R21相结果 设置：1）纵向PSU数据； 2）PSU诱导的表观遗传变化。重新连接a 耶鲁大学同类群的子样本，我们将能够评估PSU模式的轨迹 以及PSU的后果，并测试与初始的遗传因素是否相关 PSU状态预测PSU的轨迹和后果。同样，我们还将测试是否 可遗传的PSU与表观遗传变化以及这些是否介导健康结果相关。 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，提供新的治疗目标并开放新方向 在PSU的分子研究中。