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

Abstract

This study examined whether the ankyrin repeat and kinase domain containing 1 gene (ANKK1) C/T single-nucleotide polymorphism (SNP) rs1800497 moderated the association of family environment with long-term executive function (EF) following traumatic injury in early childhood. Caregivers of children with traumatic brain injury (TBI) and children with orthopedic injury completed the Behavior Rating Inventory of Executive Function (BRIEF) at post-injury visits. DNA was collected to identify the rs1800497 genotype in the ANKK1 gene. General linear models examined gene-environment interactions as moderators of the effects of TBI on EF at two times post-injury (12 months and 7 years). At 12 months post-injury, analyses revealed a significant three-way interaction of genotype with level of permissive parenting and injury type. Post hoc analyses showed genetic effects were more pronounced for children with TBI from more positive family environments, such that children with TBI who were carriers of the risk allele (T-allele) had significantly poorer EF compared with non-carriers only when they were from more advantaged environments. At 7 years post-injury, analyses revealed a significant two-way interaction of genotype with level of authoritarian parenting. Post hoc analyses found that carriers of the risk allele had significantly poorer EF compared with non-carriers only when they were from more advantaged environments. These results suggest a gene-environment interaction involving the ANKK1 gene as a predictor of EF in a pediatric injury population. The findings highlight the importance of considering environmental influences in future genetic studies on recovery following TBI and other traumatic injuries in childhood.

Progress Toward a Multiomic Understanding of Traumatic Brain Injury: A Review

“…It is important to note that each part of the multiome has a temporal dependence for turnover, and the major question of which significant biochemical alterations causally link TBI to other neurodegenerative diseases-if any-remains open. Current biomarker candidates do not provide enough information to fully understand the complex biochemical changes that ABC polymorphisms 224,225 ABC transporters mediate solute transport at the BBB ABCC8 SNPs associated with cerebral edema, ABCB1 and ABCC1 SNPs more likely to result in poor outcomes by GCS ACE 215,226,227 Regulates production of angiotensin II, which is involved in vascular remodeling, inflammation, and endothelial issues Insertion/deletion polymorphism associated with worse neuropsychological performance; three SNPs associated with worse 6-month GOS ANKK1 [228][229][230] Reduces expression of dopamine D2 receptor SNP rs1800497 associated with lower post-injury reaction time and cognitive outcomes APOE [231][232][233][234][235][236][237] Involved in neuronal membrane maintenance and repair, BBB integrity, and transport of lipids in the brain ε4 allele associated with poorer outcomes, increased inflammation and neurodegeneration, worse BBB repair, and accumulation of amyloid-β AQP4 [238][239][240] Main water channel in CNS, responsible for regulating water content of brain cells SNPs associated with poor outcomes and development of brain edema BDNF [241][242][243] Highly prevalent in CNS; normally involved in neurogenesis, glutamatergic and GABAergic signaling, and axonal regeneration post-injury val66Met substitution decreases BDNF secretion; conflicting evidence on effect on TBI outcomes COMT [244][245][246] Inactivates dopamine and noradrenaline val158Met polymorphism decreases COMT activity, leading to increased dopamine in the prefrontal cortex, and higher post-injury cognitive performance; results conflicting MME [247][248][249] Enzyme that degrades proteins including amyloid-β Longer GT repeat polymorphism associated with increased risk of plaque formation after injury; connection to AD and cerebral amyloid angiopathy TP53 ...…”

Parental warmth interacts with several genes to affect executive function components: a genome-wide environment interaction study

“…Parenting behaviors have been found to interact with genes to affect human traits like creativity [24], depression [25], aggression [26], externalizing behavior [27], self-control [28], as well as EF [16,17]. Researchers have proposed that parenting behaviors likely influence the way children cope with stress, resulting in epigenetic changes in the HPA axis such as glucocorticoid receptor expression [29] or in the neurotransmitter systems such as dopamine, oxytocin, and serotonin [30].…”

“…However, how parenting or PW specifically interacts with genes to affect EF is not well understood. Thus far, only two candidate gene studies have found that ANKK1 [16] and COMT [17] interact with parenting to affect children's EF. No GWAS, or rather Genome-Wide Environment Interaction studies (GWEIS), has been conducted on EF.…”

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

“…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).…”