Indirect association of DAT1 genotype with executive function through white matter volume in orbitofrontal cortex

The dopamine transporter (DAT1) gene has been associated with impulsivity and executive functioning. Further, DAT1 has been associated with brain structural characteristics and resting state connectivity. This study tested an indirect effect model in which DAT1 genotype (9-repeat (9R) carriers vs 10-repeat (10R) homozygotes) is linked to phenotypes representing impulsivity and executive function (planning behavior) through effects on white matter (WM) volumes in prefrontal cortex (PFC), particularly orbitofrontal cortex (OFC). Adolescents (ages 14-18, n=38) were recruited from substance use treatment (n=22) and the community (n=16) to increase phenotype variation. Results indicated that DAT1 10/10 genotype was associated with lower WM volume in the PFC, specifically the left OFC. Further, lower WM volume in the left OFC predicted more difficulties in self-reported planning behavior, but not impulsivity. Indirect effect analysis indicated that lower WM volume in the left OFC mediated the association between DAT1 10/10 genotype and difficulties in planning behavior. Results suggest a brain structural mechanism, involving lower WM volume in the left OFC, as a link in the association between DAT1 genotype and a specific aspect of executive function. Genetic effects on regional WM volume that are linked to behavioral outcomes could ultimately inform the development of tailored interventions that address an individual׳s unique risk factors.