Genetic relationships between PTSD and Alcohol Use Disorder: Integrating GWAS and Deeply Phenotyped Longitudinal data.

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Project Summary/Abstract Childhood trauma exposure, particularly in the form of interpersonal violence, increases risk for alcohol use disorder (AUD), posttraumatic stress disorder (PTSD) and their co-occurrence throughout the lifespan. AUD and PTSD frequently co-occur, and comorbidity is associated with a host of negative clinical outcomes, including greater symptom severity, poorer treatment prognosis, suicidal ideation, and poor physical health. Mechanisms of comorbidity remain largely unknown, but shared risk in the form of overlapping genetic etiology may play a role. AUD and PTSD are moderately heritable, overlap in latent genetic risk, and are genetically correlated in large GWAS studies (rG=0.35), particularly among women. In addition to genetic risk, trauma exposure may be a shared risk factor for adult AUD and PTSD, the impact of which may be exacerbated by genetic risk. However, the mechanisms by which trauma increases risk need to be identified. Preliminary evidence suggests that childhood trauma impacts brain development (i.e., atypical EEG activity observed during adolescence and young adulthood), which in turn increases risk for AUD and PTSD. Effects were more robust among females and those with a family history of AUD. Despite these promising findings, little is known about the influence of trauma on adolescent and young adult brain development and risk for AUD and PTSD, and no other studies have examined these factors together in a longitudinal paradigm, leaving the complex interactions among childhood trauma, polygenic, and neurodevelopmental risk for AUD and PTSD poorly understood. The present study will fill these gaps in the literature in a highly translational set of aims. Building of the research team’s prior work, this study will assess the impact of childhood trauma on longitudinal trajectories of brain functioning (i.e., EEG functional connectivity) and risk for adult AUD and PTSD using data from the Collaborative Study on the Genetics of Alcoholism’s prospective study. Next, using summary statistics from the largest genome wide association studies (GWAS) on AUD, AUD-related phenotypes (e.g., alcohol use behaviors) and PTSD, we will elucidate the genetic factor structure of these phenotypes. A novel multivariate genetic method, genomic Structural Equation Modeling (gSEM), will be used to determine the factor structure, and the resulting best-fit model will be used to produce polygenic risk scores (PRS) that index shared genetic risk between the phenotypes (e.g., AUD-PTSD), as well as unique risk for each condition. Finally, these PRS indexing risk unique and common for AUD-PTSD will be integrated into the longitudinal analyses of childhood trauma, EEG functional connectivity, and risk for adult AUD and PTSD. Important sex differences will also be examined. Results from this study will shed light on these important public health conditions and will yield important implications for prevention and intervention efforts.