Improving cross ancestry polygenic prediction of tobacco and alcohol use

项目总结/摘要 烟草和酒精是最常用的滥用物质，导致严重的个人和公共 医疗费用。在开始使用药物之前识别风险的能力对于预防具有重要的潜在意义 通过精准医疗方法，努力定制更有效的治疗方法。到方兴未艾的技术 基因分型的进步和成本的降低导致了遗传关联的非常大的样本量 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来告知个性化预防工作的兴趣， 人口水平的筛选，并作为统计控制或遗传工具的研究。掺入 多基因评分在临床和研究环境中的应用显示出希望，然而，其存在一些局限性。 目前的使用包括适度的预测准确性和有限的跨人群的便携性。拟议 研究将利用340万人的烟草和酒精使用的跨祖先全基因组关联研究 个体，结合约250万额外参与者的微阵列，外显子组或全基因组 测序数据，以改善对物质使用行为的多基因预测， 这些分数在不同遗传祖先的个体中的准确性。本研究的主要目的有二：1） 汇集大量不同祖先的遗传研究，包括常见和罕见的遗传信息， 变异和基因表达，以改善物质使用的基因组风险预测，以及2）评估和 校正多基因评分跨祖先可移植性降低的来源，以增加其效用 在所有遗传祖先中具有更高的预测准确性。为了实现这些研究目标， 作为一个独立的研究生涯的目标，这项建议包括新的指导培训1）先进的， 功能基因组学，2）先进的统计学和人口遗传学，3）伦理，法律的和社会影响 （ELSI）基因研究。这一建议直接符合NIDA的目标，以确定遗传机制， 并利用这项研究来解决健康差距。候选人将收到 广泛的指导和指导与领先的专家团队在成瘾，遗传学， 生命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， 一位独立的研究科学家，建立在她在定量心理学，药物成瘾， 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，临床和研究效用，并完善了我们的理解 药物使用的遗传结构。

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.