Catechol-O-Methyltransferase Genotypes and Parenting Influence on Long-Term Executive Functioning After Moderate to Severe Early Childhood Traumatic Brain Injury: An Exploratory Study

Abstract

Objective To examine Catechol-O-methyltransferase (COMT) rs4680 genotypes as moderators of the effects of parenting style on post injury changes in parent behavior ratings of executive dysfunction following moderate to severe early childhood traumatic brain injury (TBI). Setting Research was conducted in an outpatient setting. Participants Participants included children admitted to hospital with moderate to severe TBI (n = 55) or orthopedic injuries (OI; n = 70) between ages 3–7 years. Design Prospective cohort followed over seven years post injury. Main Measures Parenting Practices Questionnaire (PPQ) and the Behavior Rating Inventory of Executive Functioning (BRIEF) obtained at baseline, six, 12, and 18 months, and 3.5 and 6.8 years post injury. DNA was collected from saliva samples, purified using the Oragene (DNA Genotek, Ottawa, Ontario, Canada) OG-500 self-collection tubes, and analyzed using TaqMan (Applied Biosystems) assay protocols to identify the COMT rs4680 polymorphism. Results Linear mixed models revealed a significant genotype x parenting style x time interaction (F= 5.72, p = .02), which suggested the adverse effects of authoritarian parenting on post injury development of executive functioning were buffered by the presence of the COMT AA genotype (lower enzyme activity, higher dopamine levels). There were no significant associations of executive functioning with the interaction between genotype and authoritative or permissive parenting ratings Conclusion The lower activity COMT rs4680 genotype may buffer the negative effect of authoritarian parenting on long-term executive functioning following injury in early childhood. The findings provide preliminary evidence for associations of parenting style with executive dysfunction in children and for a complex interplay of genetic and environmental factors as contributors to decreases in these problems after traumatic injuries in children. Further investigation is warranted to understand the interplay among genetic and environmental factors related to recovery after TBI in children.

The Moderating Effect of the Ankyrin Repeat and Kinase Domain Containing One Gene on the Association of Family Environment with Longitudinal Executive Function following Traumatic Brain Injury in Early Childhood: A Preliminary Study

“…These findings add to the growing literature on genetic influences on recovery following pediatric TBI. Recent studies have found associations of the COMT genotype with long-term EF after TBI and OI 20 and of other dopamine-related genes with neurobehavioral recovery after early TBI, including ANKK1. 27 This study expands upon the limited literature by including the interaction of environment and genetic variation on outcomes of pediatric TBI.…”

“…A growing body of evidence suggests that an individual's genetic makeup may also affect recovery. While most current pediatric research on genetics in TBI has focused on the apolipoprotein E (ApoE) gene 5,18,19 and catechol-O-methyltransferase (COMT), 20 research from the adult literature suggests that genes related to preinjury cognitive capacity and reserve also may be associated with EF following TBI. 21 Much of the current research has focused on genes involved in the dopaminergic and serotonergic pathways, which are pathways often implicated in post-TBI cognitive and social impairments.…”

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

“…That is, linking gene profiles of biologic processes associated with recovery with specific gene expression and proteomic factors over time after injury (acute to chronic) would assist in characterizing when these biologic processes are most critical for recovery. For example, inflammatory processes may be critical acutely and chronically after injury (Dalla Libera et al, 2011; White et al, 2013; Juengst et al, 2015; Kumar et al, 2015; Witcher et al, 2015; McKee and Lukens, 2016; Lagraoui et al, 2017), whereas neurotransmitters and behavioral signaling may be more important primarily later after injury (McAllister, 2009; Willmott et al, 2013; Failla et al, 2015; Myrga et al, 2015, 2016; Kurowski et al, 2017a,b; Treble-Barna et al, 2017c). Characterizing these processes would be an important step toward determining when specific treatments may have the greatest impact on recovery and could also severe as a biomarker to provide a more proximal measure of treatment benefits.…”

“…Thus, to move toward a true precision medicine approach, an improved understanding how genetic and other biologic factors interact with other host, injury-related, treatment, and environmental factors to influence recovery will be critical. Age at injury, sex, and environmental factors, such as parenting style, may interact with genetic factors to influence recovery (Treble-Barna et al, 2016; Kurowski et al, 2017b; Smith-Paine et al, 2018). Prior work by our group demonstrated that, in an adverse parenting environment, a catechol-o-methyltransferase (COMT) polymorphism is protective in regards to neurocognitive functioning 18 months after pediatric TBI (Kurowski et al, 2017b) Integrating genetics, biologic, psychosocial, environmental, and individual factors into analyses to inform development of a comprehensive biopsychosocial model of recovery would allow for better development of individualized prognosis and treatment plans, but requires large-scale, collaborative, multicenter studies (Cotter et al, 2017; Kenzie et al, 2017).…”

“…Within the field of TBI recovery, narrow genetic approaches focusing on a single variant at a time have predominated (Kurowski et al, 2012, 2017a). However, emerging research suggests that recovery after TBI is a complex trait and is influenced by multiple genes plus environmental factors (McAllister, 2015; Kurowski et al, 2017a,b; Treble-Barna et al, 2017c). As such, any one variant is likely to have a relatively modest effect given the probability that good or poor recovery reflects a complex interplay of many genes, each with modest effects.…”