Iacono William G, Malone Stephen M
Department of Psychology, University of Minnesota.
Child Dev Perspect. 2011 Dec 1;5(4):239-247. doi: 10.1111/j.1750-8606.2011.00205.x.
Although substance use disorders are heritable, their complexity has made identifying genes underlying their development challenging. Endophenotypes, biologically informed quantitative measures that index genetic risk for a disorder, are being recognized for their potential to assist the search for disorder relevant genes. After outlining criteria for an endophenotype that includes developmental considerations, we review how the brain P300 response serves as an index of genetic risk for substance abuse and related externalizing disorders. The P300 response is highly heritable and associated broadly with characteristics of externalizing disorder, including childhood disruptive disorders, antisociality, and precocious expression of deviant behavior. This association appears to be mediated by shared genetic influences. Prospective studies confirm that reduced P300 amplitude present in youth prior to significant exposure to addictive substances is associated with the subsequent development of substance use disorders. Despite pronounced change in mean level over the course of development, P300 amplitude shows strong rank order stability with repeated assessment through young adulthood. In addition, P300 developmental trajectories based on multiple assessments show very high heritability and may be especially informative as measures of genetic risk. Collectively, these findings provide strong support that P300 amplitude and its change through development reflect genetic vulnerability to substance abuse and related externalizing psychopathology.
尽管物质使用障碍具有遗传性，但其复杂性使得识别其发展背后的基因具有挑战性。内表型是一种基于生物学的定量测量方法，用于衡量一种疾病的遗传风险，因其有助于寻找与疾病相关基因的潜力而受到认可。在概述了包括发育因素在内的内表型标准后，我们回顾了大脑P300反应如何作为药物滥用和相关外化障碍遗传风险的指标。P300反应具有高度遗传性，与外化障碍的特征广泛相关，包括儿童期破坏性行为障碍、反社会性和异常行为的早熟表达。这种关联似乎是由共同的遗传影响介导的。前瞻性研究证实，在大量接触成瘾物质之前，青少年中P300波幅降低与随后物质使用障碍的发展有关。尽管在发育过程中平均水平有显著变化，但通过多次评估，P300波幅在成年早期显示出很强的等级顺序稳定性。此外，基于多次评估的P300发育轨迹显示出非常高的遗传性，作为遗传风险的测量指标可能特别有意义。总体而言，这些发现有力支持了P300波幅及其在发育过程中的变化反映了对药物滥用和相关外化精神病理学的遗传易感性。
