Genetic Comorbidity of PTSD and Substance Use Disorders in Diverse Populations. - ABSTRACT/PROJECT SUMMARY Substance Use Disorders (SUD, i.e., alcohol, nicotine, cannabis, opioid) and Posttraumatic Stress Disorder (PTSD) are prevalent, highly comorbid, and associated with a high public health burden. Further, the frequent co-occurrence of SUD and PTSD has clinical implications, including greater symptom severity, poorer treatment prognosis, and poor physical health, compared to either disorder alone. Thus, there is a great need to understand their etiologic underpinnings to best inform prevention and intervention efforts. SUD and PTSD are both moderately heritable, with correlated genetic risk demonstrated by twin studies. Recent advances in statistical genetics have produced multivariate methods well suited for comorbidity applications that expand upon genetic correlations to examine causality (i.e., Mendalian Randomization [MR]), and to boost power for identification of disorder-specific and shared genetic risk (i.e., genomic structural equation modeling [gSEM]). Our work thus far has focused on the genetic relationships of PTSD with alcohol use disorder (AUD), demonstrating a significant genetic correlation between PTSD and AUD (rG=.35), and finding a support for a causal effect of PTSD on AUD. While these findings provide clues for the relationships between PTSD and other common SUD, the genetic relationships between PTSD with other SUDs, especially cannabis, and opioid use disorders remain relatively unexplored. The first aim of this project is to harness the existing large GWAS samples brought together by the Psychiatric Genomics Consortium (PGC) SUD and PTSD workgroups, to characterize the genetic relationship between SUDs and PTSD using state-of-the-science statistical genetic techniques. Initial GWAS in the PTSD and SUD workgroups have largely focused on broad phenotypes that are amendable for harmonization across cohorts. Thus, there is an unfilled need for increased data acquisition and harmonization within the workgroups to allow for more nuanced scientific questions about the PTSD-SUD relationship to be answered. For example, it is unknown if the nature of the PTSD-SUD genetic relationship is influenced by trauma characteristics (i.e., age of onset, type of trauma), differs as a function of substance use versus disorder, and how genomic risk unfolds in comorbid PTSD-SUD cases. The second aim of this project is to interrogate these more nuanced scientific questions by expanding phenotyping within the PGC groups. Importantly, existing research is limited by the under-representation of individuals of African and Latinx ancestry. The third aim of this project is to increase inclusion of diverse participants within the PTSD and SUD PGC workgroups. We will determine whether Aim 1 findings extend to populations of African and Latinx ancestry by integrating three large and diverse existing studies with data on SUD, PTSD, and trauma, and build additional collaborations to increase diversity in the PGC workgroups. The overarching goal of this proposal is to understand the genetic relationships between SUD and PTSD while increasing representation of individuals of diverse ancestry in psychiatric genetics research.
