Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach

Abstract

Objectives: To test whether genetic associations with behavioral outcomes after early childhood traumatic brain injury (TBI) are enriched for biologic pathways underpinning neurocognitive and behavioral networks. Design: Cross-sectional evaluation of the association of genetic factors with early (~ 6 months) and long-term (~ 7 years) post-TBI behavioral outcomes. We combined systems biology and genetic association testing methodologies to identify biologic pathways associated with neurocognitive and behavior outcomes after TBI. We then evaluated whether genes/single nucleotide polymorphism (SNPs) associated with these biologic pathways were more likely to demonstrate a relationship (i.e., enrichment) with short and long-term behavioral outcomes after early childhood TBI compared to genes/SNPs not associated with these biologic pathways. Setting: Outpatient research setting. Participants: 140 children, ages 3–6:11 years at time of injury, admitted for a TBI or orthopedic injury (OI). Interventions: Not Applicable. Main Outcome Measures: Child behavior checklist total problems T score. Results: Systems biology methodology identified neuronal systems and neurotransmitter signaling (Glutamate receptor, dopamine, serotonin, and calcium signaling), inflammatory response, cell death, immune systems, and brain development as important biologic pathways to neurocognitive and behavioral outcomes after TBI. At 6 months post injury, the group (TBI versus OI) by polymorphism interaction was significant when the aggregate signal from the highest ranked 40% of case gene associations was compared to the control set of genes. At ~ 7 years post injury, the selected polymorphisms had a significant main effect after controlling for injury type when the aggregate signal from the highest ranked 10% of the case genes were compared to the control set of genes Conclusions: Findings demonstrate the promise of applying a genomics approach, informed by systems biology, to understanding behavioral recovery after pediatric TBI. A mixture of biologic pathways and processes are associated with behavioral recovery, specifically genes associated with cell death, inflammatory response, neurotransmitter signaling, and brain development. These results provide insights into the complex biology of TBI recovery.

The genetic basis of inter-individual variation in recovery from traumatic brain injury

“…Recovery from TBI represents a very complex phenotype. A limitation of much work to date has been a reliance on candidate gene studies with limited numbers of patients, some of which have not proven reproducible 10 , 11 . The Genetics Association in Neurotrauma (GAIN) Consortium ( https://intbir.nih.gov/node/45 ) will produce the first GWAS to study biological mechanisms that modulate response and recovery after TBI.…”

Systems Biology Guided Gene Enrichment Approaches Improve Prediction of Chronic Post-surgical Pain After Spine Fusion

“…Scarcity of available genomic datasets for our phenotype of interest, namely, CPSP, makes GWAS daunting. Systems-biology approaches have been used successfully for identifying gene pathways implicated in other phenotypes ( Kurowski et al, 2012 ; Jegga, 2014 ; Kurowski et al, 2019 ) as they allow leveraging known genomic data sources to prioritize functional genes for association, thereby decreasing the statistical burden. In our study, literature derived training sets showed enrichment for CPSP, with genes previously known to play an important role in pain.…”

“…Case gene variants were analyzed as sequence of cumulative sums of ranked variant sets with 10% increment, as has been done in a prior study ( Kurowski et al, 2019 ). The first addend in each sequence was the training gene variant set.…”

The Emergence of Model Systems to Investigate the Link Between Traumatic Brain Injury and Alzheimer’s Disease

“…In addition to age at injury and injury severity, the pathological consequence of TBI can be influenced by a variety of genetic factors ( Wilson and Montgomery, 2007 ; Dardiotis et al, 2010 ; Bennett et al, 2016 ; Kurowski et al, 2019 ). As it relates to TBI-induced AD, polymorphisms in Apolipoprotein E (APOE) appear to be the most prominent risk-modifying genetic factor.…”