A major hurdle to studying traumatic brain injury (TBI) has been disentangling the many complicating and compounding factors that influence outcome and recovery. While extensive efforts have been placed on delineating the impact of various environmental contributions (e.g., combat exposure, mechanism of injury, etc.) on TBI outcome, the literature pertaining to the neurobiological underpinnings of poor clinical outcome in the aftermath of TBI is comparatively limited. In particular, our understanding of the influence of genetic factors on outcome and recovery following TBI is incomplete. Notably, among the studies that have examined these relationships, findings are considerably disparate, likely due to inadequate sample sizes and therefore low power to detect meaningful differences in TBI samples. Additionally, existing genetics studies have largely adopted a “candidate gene” approach, focusing on a specific gene of interest, thereby downplaying the possibility that genetic predisposition to complex traits is highly polygenic—that is, the individual contribution of a specific gene may be slight, but the effects of multiple genes could be quite significant. Thus, not only are adequately powered studies needed to better understand the influence of genetic markers on TBI clinical outcome, but a crucial next step is to apply the concept of polygenic risk to TBI and conceptualize post-injury clinical outcome as a complex polygenic phenotype. Moreover, there is accumulating evidence to suggest that the presence of neuroendocrine abnormalities may also contribute to the heterogeneous outcomes observed following TBI, yet these associations are also poorly understood. With this in mind, the present study is an observational cohort study proposing to use data available from the Million Veteran Program to examine the influence of genetic factors and neuroendocrine abnormalities on cognitive and psychiatric outcomes in Veterans with TBI histories in order to increase understanding of the extent to which neurobiological factors influence these important clinical outcomes post-TBI. Strengths of this proposal include (1) the use of large- scale genetic data to expand our understanding of neurobiological factors associated with TBI outcome, (2) the application of polygenic risk to TBI, and (3) a focus on the long-term health care outcomes of Veterans with TBI histories. Findings from this study may have particular relevance to treatments that are currently being developed and optimized within a precision medicine approach to target those most at risk of poor outcome. The applicant is currently a neuropsychology postdoctoral fellow completing the TBI/Polytrauma Fellowship at the VA San Diego Healthcare System. Successful completion of this VA Career Development Award-2 (CDA-2) will allow the candidate to advance toward a long-term career goal of being an independent clinical researcher within the VA, focused on the development of a TBI research program that ser...