PROJECT SUMMARY/ABSTRACT Cannabis has undergone widespread increases in recreational use and legalization in recent decades. Cannabis use, particularly when it begins in adolescence, is associated with impairments in multiple domains of cognition and mental health. Recently, genetic studies have found several variants associated with cannabis use and cannabis use disorder, as well as several phenotypes that are genetically correlated with cannabis use. However, it is unclear how genetic risk for cannabis use affects adolescent development and behavior, particularly in the period before substance use begins. In this project I plan to use advanced methods in statistical modeling to examine the effects of several substance use genetic risk profiles on behavior. Aim 1 of this project will test the influence of a cannabis use disorder genetic risk score, as well as several genetic risk scores known to be related to cannabis use, on multiple domains of mental health and behavior in two large samples of substance-naïve adolescents (The Adolescent Brain and Cognitive Development Study [ABCD], and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling over 115,000 participants. By incorporating multiple related genetic risk scores in univariate and multivariate statistical models, this project will be able to tease apart the unique and overlapping effects of genetic risk for cannabis use disorder compared to other genetic risk profiles. Aim 2 will follow a similar analysis technique, applied to restriction spectrum imaging measures in the brain, to understand the influence of genetic risk for cannabis use on brain microstructure in substance-naïve adolescents from the ABCD study. Finally, Aim 3 will incorporate genetic risk for cannabis use, childhood mental health measures, and brain microstructure to predict age of onset of regular cannabis use. In line with the motivation of the ABCD Study, this project will use pre-exposure data to aid in prediction of substance use behavior during adolescence. The proposed research project will leverage existing population-based longitudinal datasets to tease apart the interplay between genetic variation, brain development, and behavior. The addition of several related genetic risk scores to our statistical models will allow us to understand the shared genetic variants that contribute to brain structure and behavior. Importantly, the examination of development both before and after the initiation of cannabis use will be instrumental in understanding the relationship between cannabis use and development, and will allow us to distinguish effects that follow from cannabis use versus those that may predispose adolescents to begin using.