T21. MULTIVARIATE GENETIC RISK LINKS PTSD, SUBSTANCE USE DISORDER, AND PERSISTENT POST-CONCUSSIVE SYMPTOMS

Psychiatric sequelae such as PTSD and substance use disorder (SUD) are more likely after mild traumatic brain injury (mTBI, also known as concussion). Yet there is substantial variability in mTBI outcomes, suggesting that individual differences, including those linked to genetic risk, may play a key role. While the polygenic natures of PTSD and SUD are well-established, genetic research of mTBI and its outcomes (i.e., persistent post-concussive symptoms, PPCS) is less well-characterized, and it is unknown whether PPCS stems from common or distinct genetic factors compared to PTSD and SUD in the absence of mTBI. We seek to explain the multivariate genetic risk for mTBI/PPCS, PTSD, and SUD using both linkage disequilibrium score regression (LDSC) as well as genomic structural equation modeling (gSEM) utilizing existing large-scale mTBI/PTSD/AUD GWAS summary statistics. European ancestry LDSC shows a pattern of significant genomic correlations (rG) between PPCS, PTSD, and SUD phenotypes, including PTSD-PPCS (rG=0.32), PTSD- alcohol use disorder (AUD; rG=0.38), PPCS- AUD (rG=0.26), PTSD – Any SUD (rG=0.48), and PTSD – Opiate Use Disorder (rG=0.58). We will also present results of gSEM modeling currently underway, to decompose the multivariate genetic associations among these closely linked phenotypes. These models seek to explore the latent factor structure of genetic vulnerability for mTBI and trauma-related sequelae, identifying both shared and distinct genetic risk. Subsequent development of polygenic risk scores from the multivariate GWAS can be used for later applications in longitudinal prediction. Results would carry the promise of better understanding how latent multivariate genetic risk influences the clinical recovery for individuals impacted by mTBI, potentially identifying those most likely to benefit from comprehensive post-concussive psychiatric support.