Environment, Genes, and Temperament on the Development of Alcohol Use Disorder



 DESCRIPTION (provided by applicant): Harmful alcohol consumption is the third leading cause of preventable death in the nation.1 Among those using alcohol before the age of 18, 1 in 4 will become addicted, compared to 1 in 25 who start using at age 21.2 As such, identification of early precursors to alcohol use may delay the onset of drinking and help minimize risk for alcohol use disorder (AUD). Research to date focuses on direct associations between genes and AUD, leaving critical gaps regarding genetic pathways, relevant social contexts, and interactions between genes and the environment (GxE) underlying the etiology of AUD. The candidate's long-term goals are to: 1) achieve a greater understanding of the mechanisms influencing the onset and cause of AUD through developmentally informed interdisciplinary research; and 2) translate this knowledge into research that will uniquely contribute to the development of more mechanistically informed prevention programming. The proposed K08 Mentored Clinical Scientist Research Career Development Award seeks to address two immediate goals. The first is to redress these gaps in the AUD literature by advancing an interdisciplinary program of research on genetic, social environmental and temperamental factors underlying adolescent alcohol use using two large longitudinal datasets. Aim 1 will incorporate traits (temperament, problem behavior) as indirect developmental markers in the expression of underlying genes on AUD. Aim 2 will use high quality measurement using novel methodologies to capture a more informed assessment of social contexts. Aim 3 will assess different forms of latent GxE interactions (diathesis-stress, differential susceptibility, vantage sensitivity) on AUD. The second immediate goal is to enhance the candidate's knowledge base and research skills. The candidate plan outlines four training objectives: 1) extends knowledge in genotyping and molecular genetics; 2) develop skills in biostatistical principles and methods; 3) increase knowledge of statistical approaches for complex study designs; and 4) gain additional training in the responsible conduct of research. This training will advance the candidate's prior work examining risk factors of AUD onset by testing more comprehensive mechanistic formulations of the development of AUD by including genetic information. It will also establish her interdisciplinary program of research as an independent investigator in mechanistic processes impacting adolescent alcohol use, leading to R01 funding within the K08 award period. The project will utilize two prospective longitudinal studies, the Michigan Longitudinal Study (MLS) and The National Longitudinal Study of Adolescent Health (Add Health), as a replication sample. These datasets are unique in gathering information across extensive domains, various reporters, and multiple generations. Data include psychological, social environmental, cognitive, temperamental, and genetic factors. Few longitudinal studies combine large sample sizes, genetic and comprehensive psychosocial data, and detailed and frequent assessments over the lifespan. This allows for unique methodological opportunities to test the dynamic interplay of complex social environments and genes, and the role of temperament and problem behavior as mediators in the association between targeted genes and AUD within a prospective developmental framework. The candidate will meet these training objectives via didactics and research project completion through the mentorship and collaboration of renowned experts in the field of addiction, psychiatric genetics, biostatistics, temperament, and longitudinal study designs (Drs. Robert Zucker, Margit Burmeister, Kerby Shedden, and Joel Nigg). The rich resources available at the University of Michigan will also support her interdisciplinary program of research and facilitate her transition into an independent investigator examining adolescent AUD. This innovative application addresses the National Institute of Alcohol Abuse and Alcoholism's (NIAAA) mission as outlined in the most recent Strategic Plan: 1) the need for broad-based survey analysis; 2) researchers with strong quantitative skills; and 3) interdisciplinary research teams. Comprehensive longitudinal datasets such as the MLS and Add Health are rare; these datasets make it possible to examine the developmental course of genes, temperament, social contexts, non-specific risk factors, and their interplay on AUD across development. Moreover, the use of latent variables to reliably represent social contexts in GxE interactions is novel. This methodology allows for high-quality measurement of social influences impacting adolescent AUD across adaptive and adverse contexts. Lastly, the project will capitalize on the candidate's background in quantitative trainin, developmental psychopathology, and addiction to form an interdisciplinary partnership. This multidisciplinary approach will generate a comprehensive investigation in the role of genes, temperament, and social contexts reflecting the complexity inherent in the onset and course of adolescent AUD. It is only through these interdisciplinary teams that the maximal impact of genetics research on AUD can be realized.