Applying Systems Biology Methodology To Identify Genetic Factors Possibly Associated with Recovery after Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform a systems biology-based integrative computational analysis to ascertain the interactions between molecular components and to develop models for regulation and function of genes involved in TBI recovery. The analysis identified over-representation of genetic variants primarily in two biologic processes: response to injury (cell proliferation, cell death, inflammatory response, and cellular metabolism) and neurocognitive and behavioral reserve (brain development, cognition, and behavior). Overall, this study demonstrates the use of a systems biology-based approach to identify unique/novel genes or sets of genes important to the recovery process. Findings from this systems biology-based approach provide additional insight into the potential impact of genetic variants on the underlying complex biological processes important to TBI recovery and may inform the development of empirical genetic-related studies for TBI. Future studies that combine systems biology methodology and genomic, proteomic, and epigenetic approaches are needed in TBI.