Improving cross ancestry polygenic prediction of tobacco and alcohol use

改进烟草和酒精使用的跨血统多基因预测

• 批准号: 10739557
• 负责人: Gretchen Saunders
• 金额: $ 16.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739557
• 关键词: Address; Adoption; Affect; African; Alcohol consumption; Alcohols; All of Us Research Program; American; Award; Behavior; Behavioral Genetics; Bioethics; Clinical; Complex; Coupled; Data; Data Discovery; Data Set; Demographic Factors; Distant; Drug Addiction; Drug usage; East Asian; Equity; European; European ancestry; Exclusion; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Health Care Costs; Heritability; Heterogeneity; Human; Individual; Life Style; Linkage Disequilibrium; Medical; Mental disorders; Mentors; Mentorship; Meta-Analysis; Methods; Modeling; National Institute of Drug Abuse; Participant; Performance; Persons; Phenotype; Population; Population Genetics; Prevention; Psychology; Public Health; Research; Risk; Sample Size; Sampling; Scientist; Siblings; Smoking; Source; Structure; Substance of Abuse; Technology; Tobacco; Tobacco use; Training; Trans-Omics for Precision Medicine; United States; Variant; Veterans; Work; addiction; biobank; career; cohort; cost; disorder risk; drug use behavior; effective therapy; ethical, legal, and social implication; exome; functional genomics; genetic architecture; genetic association; genetic variant; genome sequencing; genome wide association study; genomic predictors; health disparity; improved; individualized prevention; instrument; interest; nicotine use; polygenic risk score; portability; precision medicine; preventable death; rare variant; risk prediction; risk stratification; screening; statistics; substance use; substance use treatment; trait; whole genome

Project Summary/Abstract Tobacco and alcohol are the most commonly used substances of abuse, resulting in heavy personal and public health costs. The ability to identify risk prior to substance initiation has important potential to inform prevention efforts and tailor more effective treatments through precision medicine approaches. Continuing technological progress and reduced costs of genotyping have resulted in very large sample sizes in genetic association studies, findings of which have allowed for the prediction of individual genetic risk, through polygenic risk scores. These results have ignited interest in the use of polygenic scores to inform personalized prevention efforts, population-level screening, and as statistical controls or genetic instruments within research. The incorporation of polygenic scores in clinical and research settings shows promise, however there are several limitations to their current use including modest predictive accuracy and limited portability across populations. The proposed research will leverage a trans-ancestry genome-wide association study of tobacco and alcohol use in 3.4 million individuals, combined with ~2.5 million additional participants with microarray, exome, or whole-genome sequencing data to improve polygenic prediction of substance use behaviors and to maximize predictive accuracy of such scores across individuals of diverse genetic ancestries. There are two major research aims: 1) to pool large cohorts of diverse ancestry genetic studies that include information on common and rare genetic variation, and gene expression, to improve genomic risk prediction for substance use, and 2) evaluate and correct for the sources of reduced cross-ancestry portability of polygenic scores in order to increase their utility with higher predictive accuracy across all genetic ancestries. To accomplish these research aims and to achieve the goal of an independent research career, this proposal includes new mentored training in 1) advanced and functional genomics, 2) advanced statistic and population genetics, 3) ethical, legal, and social implications (ELSI) of genetic research. This proposal directly aligns with NIDA’s goals to identify the genetic mechanisms that influence substance use and to use this research to address health disparities. The candidate will receive extensive mentorship and guidance with a team of leading experts in the fields of addiction, genetics, and bioethics. The training and support provided by this award will facilitate the candidate’s long-term career goal as an independent research scientist, building on her background in quantitative psychology, drug addiction, and behavioral genetics. The proposed research, coupled with the candidate’s research potential, has the ability to greatly expand the personal, clinical, and research utility of genomic prediction and to refine our understanding of the genetic architecture of substance use.

项目摘要/摘要 烟草和酒精是最常用的虐待物质，导致了大量的个人和公众 健康成本。在底物计划之前识别风险的能力具有为预防提供信息的重要潜力 努力并通过精确的医学方法量身定制更有效的治疗方法。继续技术 基因分型的进度和降低的成本导致了遗传关联的样本量非常大 研究，其发现允许通过多基因风险评分来预测单个遗传风险。 这些结果引起了人们对使用多基因分数来为个性化预防工作提供的兴趣， 人群级筛查，以及研究中的统计控制或遗传工具。这个行业 临床和研究环境中多基因分数显示出希望，但是它们的局限性有很多 当前使用包括适度的预测准确性和跨种群的可移植性有限。提议 研究将利用340万的烟草和酒精使用的翻译基因组协会研究 个人，与微阵列，外显子或全基因组相结合的个人，再加​​上约250万参与者 测序数据以改善物质使用行为的多基因预测并最大化预测性 在各种遗传祖先的个体中，此类得分的准确性。有两个主要的研究目的：1） 汇集大量多样性祖先遗传研究，其中包括有关常见和稀有遗传的信息 变异和基因表达，以改善使用物质使用的基因组风险预测，2）评估和评估和 纠正降低多基因分数的跨委托可移植性的来源，以提高其效用 在所有遗传祖先中具有更高的预测精度。完成这些研究的目的并实现 独立研究职业的目标，该建议包括1）高级和 功能基因组学，2）高级统计和人口遗传学，3）道德，法律和社会影响 （ELSI）遗传研究。该建议直接与NIDA的目标保持一致，以确定遗传机制 这会影响物质使用，并利用这项研究来解决健康分布。候选人将收到 在成瘾，遗传学和 生物伦理学。该奖项提供的培训和支持将有助于候选人的长期职业目标 一位独立的研究科学家，基于定量心理学，药物成瘾和 行为遗传学。拟议的研究以及候选人的研究潜力，具有 大大扩展了基因组预测的个人，临床和研究实用性，并完善我们的理解 物质使用的遗传结构。