Phenotyping, Genotyping, and Risk Prediction of TBI-Related Variables and Comorbidities in Military Veterans Enrolled in MVP

Va San Diego Healthcare System, San Diego CA

Investigators

Abstract

Military personnel serving in Iraq and Afghanistan have sustained traumatic brain injuries (TBIs) at a higher frequency than prior conflicts, prompting widespread interest in the assessment and management of TBI and its associated sequelae. Veterans with a history of TBI often report numerous neurobehavioral or “post- concussive” symptoms following injury (e.g., vestibular, somatic, cognitive, and affective-related symptoms), experience high rates of mental health comorbidities (e.g., posttraumatic stress disorder [PTSD], depression), and develop a wide range of functional limitations (e.g., difficulties finding and maintaining employment, high rates of disability). The costs associated with TBI assessment and management are also substantial, with estimates showing that the median annual healthcare cost per patient was approximately four times higher for Veterans with a history of TBI compared to Veterans without a history of TBI. Despite substantial gains in our knowledge of factors that contribute to these debilitating outcomes, there remain critical gaps in our understanding of the spectrum of risk factors associated with poor outcome and recovery following TBI. While environmental and genetic factors have both been shown to influence post-TBI outcome and recovery, the literature pertaining to genetic predisposition to poor clinical outcomes following TBI is rudimentary. Our group recently conducted the first-ever large-scale genome-wide association study (GWAS) of TBI within the VA Million Veteran Program (MVP). We showed that TBI is a heritable, polygenic disorder and identified numerous genome-wide significant risk loci, including several interesting targets with respect to the biology of TBI. These findings have laid the groundwork for future TBI GWASs that focus directly on diversity and chronicity of signs and symptoms associated with TBI. We now wish to continue this project by expanding our phenotyping and genetic characterization efforts to explore additional, more nuanced, TBI-related variables and comorbidities within MVP. Ultimately, we aim to better understand the combination of environmental and genetic factors that increase risk for poor outcome following TBI in military Veterans. In Aim 1, we will develop TBI-related phenotypes (i.e., TBI severity, VA TBI Screening and Evaluation Program diagnoses, persistent post-concussive symptoms [PPCS], and TBI/mental health comorbidities). We will also complete characterization studies to further delineate the phenotypes of interest. In Aim 2, we will conduct GWASs on the TBI phenotypes, identify functional consequences of variants identified in GWASs, discern the genetic architecture of the phenotypes, and examine how different TBI phenotypes relate to psychiatric and cognitive traits. Finally, Aim 3 will identify which risk factors—environmental and/or genetic— are most associated with clinical outcomes following TBI and will develop clinically relevant risk prediction models. All aims will be carried out using MVP data. A key advantage of utilizing MVP data for this study is that MVP affords a unique opportunity to address and go beyond methodological limitations of previously published studies by offering a voluminous sample size of TBI-exposed Veterans, the availability of comprehensive phenotypic and genetic data, as well as access to Veterans’ electronic health record—all of which will contribute to the scientific rigor of our findings. This project represents several new areas of scientific advancement that have great potential to significantly impact Veterans’ health. As TBI represents one of the more common injuries of the Iraq and Afghanistan conflicts, there is, and will continue to be, considerable need to understand TBI and its associated sequelae in military Veterans. Ultimately, study findings will help to inform interventions and treatments that are being developed and optimized within a precision medicine approach, and findings may also direct future pharmaceutical research aimed at effective treatments for Veterans with PPCS and mental health comorbidities following TBI.