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

Brad G. Kurowski,Keith Owen Yeates,Shari L. Wade,Lisa J. Martin,Valentina Pilipenko,Anil G. Jegga,Amery Treble-Barna,H. Gerry Taylor

doi:10.3389/fgene.2019.00481

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 genesConclusions: 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.

Highlights

Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality in children and young adults (Bruns and Hauser, 2003; Faul et al, 2010; Faul and Coronado, 2015; Popernack et al, 2015; Taylor et al, 2017)
Based on a systematic review of primarily candidate gene association studies in the TBI literature and a systems biology informatics approach, we previously identified overrepresentation of gene variants in two primary biologic processes related to broad clinical outcomes following TBI: response to injury and neurocognitive and behavioral reserve (Kurowski et al, 2017a)
The results of this study suggest that behavioral outcomes after early childhood TBI are associated with a combination of genes underpinning an array of biologic processes, including immune system functioning, inflammatory response, cell death, neurotransmitter signaling, and brain development

Summary

Introduction

Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality in children and young adults (Bruns and Hauser, 2003; Faul et al, 2010; Faul and Coronado, 2015; Popernack et al, 2015; Taylor et al, 2017). Research on the association of genetic factors with behavioral and cognitive outcomes after TBI is growing, in both adults and children (Diaz-Arrastia and Baxter, 2006; Jordan, 2007; Dardiotis et al, 2010; McAllister, 2010, 2015; Kurowski et al, 2012; Weaver et al, 2012; Davidson et al, 2014; Lipsky and Lin, 2015; Kassam et al, 2016). Prior work demonstrated associations of inflammatory, dopamine, neuroplasticity, cognitive, and cell metabolism-related genes and polymorphisms with outcomes after brain injury (Weaver et al, 2012; McAllister, 2015; Kurowski et al, 2017a). Alternative approaches that consider multiple genes or polymorphisms are needed to characterize the role of genetic factors in outcomes after brain injury. Studies of genetic association for complex traits indicate that multiple biologic pathways are likely to underlie any given genetic association (Hirschhorn, 2005)

Objectives

Results

Discussion

Conclusion