PROJECT SUMMARY/ABSTRACT Alcohol is the most widely used substance and the third-leading preventable cause of death in the United States. Initiation of alcohol use typically occurs in adolescence, and early onset alcohol use (< age 15) has been associated with prolonged negative outcomes such as increased risk for AUD. The development of alcohol use and AUD is influenced by genetic and environmental factors, and the complex interactions among them (i.e., gene-environment interaction or GE). Yet, the majority of genetic and GE research has been 1) conducted with populations of European ancestry, and 2) focused on alcohol outcomes among individuals who have already initiated alcohol use or developed AUD. Thus, there is limited understanding of GE processes in racially-ethnically diverse populations, and how genetic risk manifests earlier in development in order to inform early prevention and intervention efforts. Furthermore, despite culture being an important context that shapes human behavior, cultural risk and protective factors have been largely overlooked in GE research. We seek to advance the understanding of etiology of alcohol use and AUD among racially-ethnically diverse populations by taking a developmentally and culturally informed approach to study GE processes. This project draws data from the ongoing Adolescent Brain and Cognitive Development (ABCD) Study, which includes rich genomic and phenotypic data from a longitudinal sample (N = 11,875; 52.1% White, 15.0% Black, and 20.3% Hispanic/Latinx) of racially-ethnically diverse children from late childhood (9-10 years old) through adolescence. The project examines three research aims. First, we will characterize polygenic influences on adolescent alcohol use among racially-ethnically diverse youth. Using a genome-wide polygenic score (PRS) approach, we will examine the effects of multiple adult and child-based PRS for alcohol and related traits (e.g., externalizing, internalizing symptoms) on timing of progression through the stages (e.g., experimentation, initiation, regular use, and problematic use), and trajectories of alcohol use from late childhood to adolescence. Second, we will examine the role of multiple childhood precursors (i.e., impulsivity, externalizing, and internalizing symptoms) in mediating polygenic influences on alcohol use. Finally, we will investigate the role of cultural-contextual risk and protective factors (i.e., parenting, peer deviance, stressful life events, racial discrimination experiences, familism cultural value) in moderating genetic influences on childhood precursors and adolescent alcohol use. We will explore how the associations of genetic, cultural-contextual factors, childhood precursors, and alcohol use change from late childhood to adolescence by examining age and developmental differences, and exploring differences by sex and pubertal status. Findings will advance alcohol and health disparities sciences by elucidating developmental and environmental mechanisms linking genetic risk to alcohol use among racially-ethnically diverse adolescents, providing critical insights for alcohol use prevention and intervention programs, including who is most at risk, what to target, and when to intervene.

PROJECT NARRATIVE Alcohol use and disorders are prevalent and associated with significant personal, interpersonal, and societal costs. Relevant to NIH's public health mission, the proposed study investigates genetic influences on the progression and trajectories of alcohol use from late childhood to adolescence, examines the role of childhood precursors (impulsivity, externalizing, and internalizing symptoms) in the pathways of genetic risk to alcohol use, and identifies cultural-contextual risk and protective factors that moderate genetic risk among racially- ethnically diverse youth. Findings have strong potential to inform culturally-tailored and personalized early prevention programs aimed at reducing alcohol problems and related health disparities.