Project Summary/Abstract Sexual minority (i.e., lesbian, gay, bisexual, and mostly heterosexual) young people in the U.S. have elevated risk of substance use and adverse mental health outcomes compared to their heterosexual peers. These health inequities may be the result of social stressors such as stigma and discrimination that can influence health at multiple levels, including individual (e.g., interpersonal discrimination) and structural levels (e.g., discriminatory state policies). Yet little is known about how these individual- and structural-level social stressors or resilience factors (e.g., social support) contribute to health inequities in substance use and how they affect health-related quality of life (HRQOL). There is a pressing need to understand (i) how changes over time in structural discrimination (e.g., law and policy) may relate to substance use and HRQOL across sexual orientation groups and (ii) heterogeneity within sexual minorities, such as patterning of multi-level stressors across race/ethnicity, gender (including gender nonconformity, which can be a target for discrimination), and age cohort. To address these research imperatives, this project will focus on the following aims: (1) Examine the interplay between structural-level stressors and sexual orientation in the development of substance use and HRQOL. Using longitudinal cohort data and a state-level database of changes in laws and policies relevant to sexual minority civil rights, analyses will examine effect modification of the association between sexual orientation and substance use and HRQOL by state-level structural discrimination over the course of adolescent development. (2) Elucidate the relationships between structural- and individual-level stressors and substance use and HRQOL among diverse sexual minorities, using data from two complementary national cohorts of sexual minorities. Analyses will compare associations between state-level structural discrimination, self- reported experiences of discrimination, resilience factors, and risk of substance use and poor HRQOL and will examine differential patterning of social stressors by race/ethnicity, gender nonconformity, and age cohort. To achieve these aims the research will utilize data from (i) the Growing Up Today Study, a longitudinal cohort of 27,000 youth who were recruited when they were ages 9-14 and are now in their 20s-to-30s, and (ii) the Generations Study, a national probability sample of 676 U.S. Black, Latino and White sexual minorities in three age cohorts, representing generations that came of age in disparate social and policy environments with regards to sexual orientation. Longitudinal statistical methods and structural equation modeling will be used to examine the above aims. The proposed research will be among the first to examine multilevel U.S. social and policy contexts in relation to sexual orientation inequities in substance use and HRQOL. Findings will enhance understanding of key mechanisms in the development of sexual orientation-related health inequities and will inform interventions to mitigate stressors and strengthen protective factors for sexual minority youth.