The Kinship Risk Score: An Integrative Tool to Prioritize Alcohol and Drug-Addiction Related Genes for Enhanced Risk Prediction

亲属关系风险评分：优先考虑酒精和毒瘾相关基因以增强风险预测的综合工具

• 批准号: 10212359
• 负责人: ROHAN Hugh Craig PALMER
• 金额: $ 46.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212359
• 关键词: ATOD; Addictive Behavior; Alcohol dependence; Alcohols; Animals; Bayesian Analysis; Behavior; Behavioral; Biological; Complement; Complex; Data; Dependence; Development; Disease; Drug Addiction; Ethnic group; Family Study; Genes; Genetic; Genetic Variation; Genomics; Goals; Health; Human; Individual Differences; Mendelian disorder; Modeling; Molecular; Pathway interactions; Predisposition; Prevention; Relative Risks; Research; Risk; Specific qualifier value; Substance Addiction; Testing; Tobacco; Twin Studies; Variant; addiction; alcohol and other drug; base; combinatorial; drug of abuse; flexibility; functional genomics; gene interaction; genetic variant; genome-wide; genomic locus; illicit drug use; improved; novel; online resource; polysubstance abuse; predictive modeling; psychosocial; risk prediction; tool; trait

PROJECT SUMMARY/ABSTRACT The primary goals of this project are to identify and characterize gene sets that reflect individual differences in the propensity to develop alcohol or other forms of drug addiction and to develop a novel tool to enhance the prediction of drug addiction risk using genome-wide data. Alcohol, tobacco, and illicit drug use and dependence are complex biological and psychosocial problems that can be conceptualized as alternate forms of an underlying behavioral predisposition to the development of generalized drug dependence (DD). Despite the fact that twin and family studies suggest that genetic variation contributes to the preoccupation with alcohol and other multiple substances of abuse, the identification of specific causal loci has been limited. In fact, studies have confirmed that unlike monogenic disorders, alcohol and other drugs of abuse are influenced by numerous genetic variants. While both human and animal studies of addiction have indicated that multiple forms of drug addiction are genetically influenced, the full complement of biological mechanisms and genetic factors are still unknown. The current application proposes a novel framework and tool that integrates Bayesian statistics and functional genomics to enhance the identification of a set(s) of causal genetic factors for alcohol and other drug dependence. In the first component of the framework, we will use Bayesian mixture modeling to identify a set(s) of markers that comprise the additive genetic effect on generalized drug dependence (DD). In the second component, we will identify cross-species-functionally-annotated gene sets for alcohol, tobacco, and other illicit drug use/dependence, determine their relative contribution to variation in DD, and test for enrichment of the Bayesian-derived gene set(s) in (a) gene sets ascertained using cross- species-functional genomic studies of alcohol and other drug addiction, and (b) a range of biological gene sets based on known molecular pathways. In the third component, we will identify combinatorial effects within and between gene sets. In the final component, we develop prediction models, as well as test a novel kinship- based approach to predict the risk for DD given a specified gene set. Each of these components provides novel information that will help to formulate new research hypotheses and prediction models for addictive behaviors and other behaviors/traits.

项目摘要/摘要 该项目的主要目标是识别和表征反映个体差异的基因集 开发酒精或其他形式的药物成瘾的倾向，并开发一种新颖的工具来增强 使用全基因组数据预测药物成瘾风险。酒精，烟草和非法吸毒和 依赖性是复杂的生物学和社会心理问题，可以概念化为替代形式 对广义药物依赖性（DD）发展的潜在行为倾向。尽管 双胞胎和家庭研究表明遗传变异的事实有助于对酒精的关注 和其他多种滥用物质，特定因果基因座的识别受到限制。实际上， 研究已经证实，与单基因疾病不同，酒精和其他滥用药物受到影响 许多遗传变异。尽管人类和动物的成瘾研究都表明多个 药物成瘾形式受到遗传影响，生物学机制的完整补体和遗传 因素仍然未知。当前的应用程序提出了一个集成的新型框架和工具 贝叶斯统计和功能基因组学以增强因果遗传因素的识别 用于酒精和其他药物依赖。在框架的第一个组件中，我们将使用贝叶斯混合物 建模以识别构成对广义药物添加遗传作用的标记集 依赖性（DD）。在第二个组件中，我们将确定跨物种 - 功能宣布的基因集 对于酒精，烟草和其他非法药物使用/依赖性，请确定它们对变异的相对贡献 DD，以及（a）基因集中贝叶斯衍生基因集的富集的测试 酒精和其他药物成瘾的物种功能基因组研究，以及（b）一系列生物学基因集 基于已知的分子途径。在第三个组件中，我们将确定内部和 在基因组之间。在最终组件中，我们开发了预测模型，并测试了一种新型的亲属关系。 基于指定基因集预测DD风险的方法。这些组件中的每一个都提供 新的信息将有助于制定新的研究假设和预测模型 行为和其他行为/特征。

项目成果

Associations between neuroticism, subjective sleep quality, and depressive symptoms across the first year of college.

• DOI: 10.1080/07448481.2021.1891917
• 发表时间: 2023-03
• 期刊: Journal of American college health : J of ACH
• 作者: Catherman C;Cassidy S;Benca-Bachman CE;Barber JM;Palmer RHC
• 通讯作者: Palmer RHC

Adolescent Behavioral Characteristics Mediate Familial Effects on Alcohol Use and Problems in College-Bound Students.

• DOI: 10.1177/1178221820970925
• 发表时间: 2020
• 期刊: Substance abuse : research and treatment
• 作者: Brown AL;España RA;Benca-Bachman CE;Welsh JW;Palmer RH
• 通讯作者: Palmer RH

Genome- and transcriptome-wide splicing associations with alcohol use disorder.

• DOI: 10.1038/s41598-023-30926-z
• 发表时间: 2023-03-09
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Huggett, Spencer B.;Ikeda, Ami S.;Yuan, Qingyue;Benca-Bachman, Chelsie E.;Palmer, Rohan H. C.
• 通讯作者: Palmer, Rohan H. C.

On the utilization of the induced pluripotent stem cell (iPSC) model to study substance use disorders: A scoping review protocol.

• DOI: 10.1371/journal.pone.0292238
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7