Improving cross ancestry polygenic prediction of tobacco and alcohol use

项目摘要/摘要 烟草和酒精是最常用的滥用物质，对个人和公众造成严重危害 医疗费用。在物质启动之前识别风险的能力对预防具有重要的潜在意义 通过精准医学方法努力并量身定做更有效的治疗方法。持续技术 基因分型的进步和成本的降低导致了基因关联中非常大的样本量 研究结果允许通过多基因风险评分预测个体遗传风险。 这些结果激发了人们对使用多基因评分为个性化预防工作提供信息的兴趣， 人口一级的筛查，以及作为研究中的统计控制或遗传工具。成立为法团 多基因评分在临床和研究环境中显示出希望，但其有几个限制 目前的使用包括适度的预测准确性和有限的跨人群便携性。建议数 研究将利用340万人中烟草和酒精使用的跨祖先全基因组关联研究 个人，加上约250万具有微阵列、外显子组或全基因组的额外参与者 测序数据以改进物质使用行为的多基因预测并最大化预测 这些分数在不同基因祖先的个体中的准确性。主要研究目标有两个：1) 汇集大量不同祖先的基因研究，包括常见和稀有基因的信息 变异和基因表达，以改进对药物使用的基因组风险预测，以及2)评估和 纠正多基因遗传标记交叉可携带性降低的来源，以增加其实用性 在所有基因祖先中具有更高的预测准确性。为了实现这些研究目标并实现 作为独立研究事业的目标，这项建议包括在1)高级和 功能基因组学，2)高级统计学和人口遗传学，3)伦理、法律和社会影响 (ELSI)的基因研究。这一建议与NIDA确定遗传机制的目标直接一致 影响物质使用的因素，并利用这项研究解决健康差距问题。应聘者将收到 广泛的指导和指导团队的领先专家在成瘾，遗传学和 生物伦理学。该奖项提供的培训和支持将促进候选人的长期职业目标，如 一位独立的研究科学家，以她在数量心理学、吸毒成瘾和 行为遗传学。拟议的研究，加上候选人的研究潜力，有能力 极大地扩展了基因组预测的个人、临床和研究用途，并完善了我们的理解 物质使用的遗传结构。

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.