Longitudinal neuroimaging and statistical genetics modeling of substance use and trauma-related phenotypes

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PROJECT SUMMARY Childhood and early adolescence are especially vulnerable developmental stages where experiencing traumatic events (TEs) would increase the liability and risk for developing posttraumatic stress disorders (PTSD) and substance use (SU) disorder (SUD) later in life. These phenotypes frequently co-occur, and this comorbidity is associated with increased negative outcomes (e.g. decreased social function and treatment compliance, increased risk for violence and suicidal ideation/attempts). Given the complex and multifactorial etiology of these conditions, there is a need for multimethod studies aimed at increasing the understanding of their etiology including genetic and neurodevelopmental factors. Thus far, studies investigating the genetic factors and brain regions of interest (ROIs) thought to influence these phenotypes have largely focused on adults and the majority have been cross-sectional. For this reason, we will use a large (N=11,878) longitudinal sample (Adolescent Brain Cognitive Development [ABCD] study, site-PIs: Drs. Neale and Bjork) to investigate, via Aim 1, the occurrence and type of TEs, other risk factors (e.g., conduct disorder symptoms, parental style; see Research Strategy C.3 section), and their influence on PTSD-symptoms and SU-phenotypes development from childhood to early adolescence. Aim 2 will utilize structural magnetic resonance imaging longitudinal data to estimate statistics of the mediational role of alterations of volume of brain ROIs on the trajectories of PTSD-symptoms and SU- phenotypes. Finally, as SUD and PTSD are moderately heritable, Aim 3 will assess the genetic architecture (e.g. GWAS), generate and use polygenic risk scores to investigate the etiology, trajectories, strength and direction of the relationships across time influencing the early signs and development of PTSD-symptoms and SU- phenotypes. Both molecular genetic and phenotypic analyses (including GCTA, LDSC, Cross-Lagged Panel Analysis, Genome-Wide Structural Equation Modeling) will be applied. This proposal has four training goals to be met via a multi-modal training plan. The first training goal is to develop a deeper scientific knowledge and expertise in PTSD and SUD phenotypes. Second is to become knowledgeable in neuroimaging research and its intersection with genetics and psychopathology. The third goal is to expand proficiency in advanced molecular and statistical genetics modeling. Fourth is to increase professional development training that will enhance academic proficiency. This project is intended to extend the understanding of the contribution of etiological factors (genetic, neurodevelopmental, environmental) and processes involved in the development of PTSD- symptoms and SU-phenotypes during childhood and early adolescence, and offer insights for clinical applications—strategic prevention and treatment of PTSD and SUD. This NRSA proposal aligns with the mission of the National Institute on Drug Abuse (NIDA) on advancing scientific research, by investigating the etiology, trajectories and mechanisms of PTSD-symptoms and SU-phenotypes longitudinally in understudied developmental stages. It also aims to influence the improvement of individual and collective health.