Exploring polygenic risk as a means for personalizing TBI rehabilitation

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Mild traumatic brain injury (mTBI) is a signature disorder of recent conflicts in Iraq and Afghanistan, with over 300,000 service members receiving a first-time mTBI diagnosis since 2000. Though the majority of mTBI cases do see a return to normal functioning, a so-called “miserable minority” experience persistent symptoms of post-concussive syndrome (PCS) that can result in prolonged impairment. For these individuals, rehabilitative interventions are frequently ineffective. Identifying biological factors that might confer risk for persistent symptoms and/or factors that might predict rehabilitative outcomes would be a critical step towards enhancing the personalization and optimization of rehabilitative care for mTBI. A growing literature suggests that the persistence of PCS symptoms may be linked to factors separate from the head injury itself, including premorbid/comorbid psychopathology. As such, factors associated with vulnerability for psychopathology, such as genetics, likely confer risk for sub-optimal recovery following mTBI. Recent advances in large-scale genome-wide association studies (GWASs) have helped characterize genetic vulnerability for a wide range of disorders. Building off of these advances, we can use GWAS results to calculate polygenic risk scores (PRSs), which calculate an individual's cumulative genetic risk for a given disorder or trait by summing the number of risk alleles across the entire genome, weighted by each allele's relative risk. Cross- disorder validation using PRS (i.e. using PRS from one disorder/trait to predict the prevalence of another disorder/trait within the same person) has been used to identify shared genetic etiology between putatively- related conditions. Therefore, PRS scores derived from mTBI-related conditions could pave the way for a more robust understanding of how genes moderate mTBI recovery. The proposed study will collect genome-wide data on veterans with a history of mTBI from two sources. The first will be local sample of 1000 veterans referred for mTBI treatment through the Minneapolis VA Health Care System (MVAHCS) Physical Medicine and Rehabilitation service and Polytrauma Rehabilitation Center. The second will be veterans assessed for mTBI in two large-scale consortia efforts: the Psychiatric Genomics Consortium-PTSD Working Group (PGC-PTSD) and the Chronic Effects of Neurotrauma Consortium (CENC). For all participants, we will derive PRSs from GWAS data linked to nine disorders/traits that are theorized to be related to mTBI outcomes. These disorders/traits fall into the following broad categories: psychological (posttraumatic stress disorder, major depressive disorder, attention deficit-hyperactivity disorder, cross-disorder risk), neurological (Alzheimer's Disease, Parkinson's Disease), cognitive (educational attainment, childhood intelligence), and subjective (subjective well-being). Aim 1 of the proposed study will determine the association between PRSs and the presence of persistent PCS symptoms in local and consortia samples, with an exploratory follow-up (Aim 1A) using each individual's history of traumatic events as an environmental stressor in a polygenic gene-by-environment interaction analysis. Aim 2 will use PRSs to predict treatment response in veterans referred for treatment of mTBI-related symptoms (including management of PCS or PTSD). Exploratory aim 3 will conduct a phenome-wide association study using a wide variety of phenotypic data extracted from computerized records (including diagnoses, health factors, and neural indices). This approach can be used to identify plausible intermediate phenotypes, which would shed light on mechanisms by which genetic risk is conferred. The proposed project would be the largest to look at genetic factors associated with PCS and the first to look at genetic factors associated with mTBI rehabilitation. The results of this project could be directly interpretable as a personalized genetic profile for mTBI recovery, which could substantially improve the precision and effectiveness of rehabilitative care for mTBI sequelae.