Cumulative Influence of Inflammatory Response Genetic Variation on Long-Term Neurobehavioral Outcomes after Pediatric Traumatic Brain Injury Relative to Orthopedic Injury: An Exploratory Polygenic Risk Score

Abstract

The addition of genetic factors to prognostic models of neurobehavioral recovery following pediatric traumatic brain injury (TBI) may account for unexplained heterogeneity in outcomes. The present study examined the cumulative influence of candidate genes involved in the inflammatory response on long-term neurobehavioral recovery in children with early childhood TBI relative to children with orthopedic injuries (OI). Participants were drawn from a prospective, longitudinal study evaluating outcomes of children who sustained TBI (n = 67) or OI (n = 68) between the ages of 3 and 7 years. Parents completed ratings of child executive function and behavior at an average of 6.8 years after injury. Exploratory unweighted and weighted polygenic risk scores (PRS) were constructed from single nucleotide polymorphisms (SNPs) across candidate inflammatory response genes (i.e., angiotensin converting enzyme [ACE], brain-derived neurotrophic factor [BDNF], interleukin-1 receptor antagonist [IL1RN], and 5'-ectonucleotidase [NT5E]) that showed nominal (p ≤ 0.20) associations with outcomes in the TBI group. Linear regression models tested the PRS × injury group (TBI vs. OI) interaction term and post-hoc analyses examined the effect of PRS within each injury group. Higher inflammatory response PRS were associated with more executive dysfunction and behavior problems in children with TBI but not in children with OI. The cumulative influence of inflammatory response genes as measured by PRS explained additional variance in long-term neurobehavioral outcomes, over and above well-established predictors and single candidate SNPs tested individually. The results suggest that some of the unexplained heterogeneity in long-term neurobehavioral outcomes following pediatric TBI may be attributable to a child's genetic predisposition to a greater or lesser inflammatory response to TBI.

Keywords: PRS; TBI; behavior; inflammatory response; pediatric brain injury.

FIG. 1.

Association of unweighted (A and C) and weighted (B and D) inflammatory response polygenic risk scores (PRS) with long-term executive function (A and B) and behavioral adjustment (C and D) in children with traumatic brain injury (TBI) or orthopedic injury (OI). There are increasing executive dysfunction and behavior problems with increasing unweighted and weighted PRS in children with TBI but no association between PRS and outcome in children with OI.