Improving cross ancestry polygenic prediction of tobacco and alcohol use

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.