Chung Tammy, Ferrell Robert, Clark Duncan B
Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
Psychiatry Res. 2015 Apr 30;232(1):76-83. doi: 10.1016/j.pscychresns.2015.01.021. Epub 2015 Feb 4.
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.
多巴胺转运体（DAT1）基因与冲动性和执行功能有关。此外，DAT1还与脑结构特征和静息态连接性有关。本研究测试了一种间接效应模型，其中DAT1基因型（9重复序列（9R）携带者与10重复序列（10R）纯合子）通过对前额叶皮质（PFC），特别是眶额皮质（OFC）的白质（WM）体积的影响，与代表冲动性和执行功能（计划行为）的表型相关联。从物质使用治疗组（n = 22）和社区（n = 16）招募青少年（14 - 18岁，n = 38）以增加表型变异。结果表明，DAT1 10/10基因型与PFC中较低的WM体积相关，特别是左侧OFC。此外，左侧OFC中较低的WM体积预示着自我报告的计划行为会有更多困难，但与冲动性无关。间接效应分析表明，左侧OFC中较低的WM体积介导了DAT1 10/10基因型与计划行为困难之间的关联。结果提示一种脑结构机制，涉及左侧OFC中较低的WM体积，作为DAT1基因型与执行功能特定方面之间关联的一个环节。与行为结果相关的对区域WM体积的遗传效应最终可能为制定针对个体独特风险因素的量身定制干预措施提供信息。
