Genetic Influences of Dopamine and GABA on Adolescent Cognition

Abstract

Adolescence is a time of exploration, but also risk taking, such as alcohol use. What places individuals’ at risk has not been fully elucidated. Twin studies of adult alcohol use disorders (AUD’s) found genetics account for around 60% of the variability. Numerous genetic association studies have been done, though most investigated linkage with genetic loci; not how loci confer risk. If genes associated with adult AUD’s have impact during adolescence and alcohol use initiation, it’s likely they impact cognitive functioning, predisposing adolescents to such risky decision-making. Three genetic polymorphisms associated with adult AUD’s are the C allele of C957T in the dopamine receptor D2 gene (DRD2), the 10 repeat allele (10R) of the 40 bp VNTR in the dopamine transporter gene (DAT1), and the G allele of rs279826 in the GABA-A receptor α2 subunit gene (GABRA2). The current investigation longitudinally investigated these polymorphisms on adolescent cognitive functioning using fMRI. This included inhibitory control (Go-NoGo task), attentional bias (ecStroop task), and risky decision-making/reward response (WoF task). fMRI analyses included activation differences and functional connectivity. Lastly, genetic influence on alcohol use initiation was investigated. It was hypothesized risk alleles had lower inhibitory control, greater attentional bias, risky decision-making, reward response, and risk to alcohol use initiation. DRD2 suggested the C allele had less neural efficiency during the Go-NoGo and WoF. They were less accurate during the ecStroop, and became more neuronally reactive to stimuli as they aged. DAT1 only affected WoF, with 10R making more risky decisions, having less neural efficiency and greater response to reward. Results for GABA were opposing, suggesting the lower risk A allele had lower neuronal efficiency during the Go-NoGo and ecStroop, while the G allele made more risky decisions, had less neural efficiency and greater response to reward during the WoF. However, two results suggest developmental effects during the ecStroop, in that cognitive control for the G allele decreases over adolescence. Lastly, no polymorphism was associated with alcohol use initiation. Though this study found no association with alcohol use initiation, it supports the proposition of studying genetic effects associated with adult AUD’s on adolescent cognitive function.