Barkley Russell A, Smith Karen M, Fischer Mariellen, Navia Bradford
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York, USA.
Am J Med Genet B Neuropsychiatr Genet. 2006 Jul 5;141B(5):487-98. doi: 10.1002/ajmg.b.30326.
Several candidate gene polymorphisms have been implicated in attention deficit hyperactivity disorder (ADHD), including DAT1 40bp VNTR, DRD4 7+, and DBH TaqI A2 alleles. We used the Milwaukee longitudinal study of hyperactive (n = 122) and normal (n = 67) children to compare participants with and without these respective polymorphisms on ADHD-related behavioral ratings at childhood, 8 years later in adolescence, and 13+ years later into young adulthood. Neuropsychological tests were given at the adolescent and young adulthood follow-up. No differences were found between the DRD4-7+ and 7- repeat polymorphism. The DBH TaqI A2 allele, when homozygous, was associated with being more hyperactive in childhood, having more pervasive behavior problems at adolescence, and earning less money on a card playing task in adulthood. At adolescence, poorer test scores were also found only in the hyperactive group with homozygous for this allele. The DAT1 40bp VNTR heterozygous 9/10 repeat, however, differed from the 10/10 repeat pair in many respects, having greater ADHD and externalizing symptoms at all three follow-ups, more cross-situational behavioral problems at both childhood and adolescence, poorer mother-teen relations at adolescence, and lower class rankings in high school. Participants with the 9/10 pair in the control group also had lower work performance, a lower grade point average in high school, greater teacher rated externalizing symptoms at adolescence, and greater omission errors on a continuous performance test in adulthood. The DAT1 40bp VNTR 9/10 polymorphism pairing appears to be reliably associated with greater symptoms of ADHD and externalizing behavior from childhood to adulthood, and with family, educational, and occupational impairments. We also present a contrary view on the appropriate endophenotypes for use in behavioral genetic research on ADHD.
几种候选基因多态性与注意力缺陷多动障碍(ADHD)有关,包括多巴胺转运体1(DAT1)基因40bp可变数目串联重复序列(VNTR)、多巴胺D4受体(DRD4)基因7次重复等位基因以及多巴胺β羟化酶(DBH)基因TaqI A2等位基因。我们利用对多动儿童(n = 122)和正常儿童(n = 67)的密尔沃基纵向研究,比较了有无这些多态性的参与者在儿童期、8年后的青少年期以及13年多后的青年期与ADHD相关的行为评分。在青少年期和青年期随访时进行了神经心理学测试。未发现DRD4基因7次重复与非7次重复多态性之间存在差异。DBH基因TaqI A2等位基因纯合时,与儿童期多动更明显、青少年期存在更多普遍性行为问题以及成年期在纸牌游戏任务中赚钱较少有关。在青少年期,仅在该等位基因纯合的多动组中发现测试成绩较差。然而,DAT1基因40bp VNTR杂合的9/10重复序列在许多方面与10/10重复序列对不同,在所有三次随访中具有更严重的ADHD和外化症状,在儿童期和青少年期均存在更多跨情境行为问题,青少年期母子关系较差,高中班级排名较低。对照组中具有9/10重复序列对的参与者工作表现也较低,高中平均绩点较低,青少年期教师评定的外化症状更严重,成年期在持续性操作测试中的遗漏错误更多。DAT1基因40bp VNTR 9/10多态性配对似乎与从儿童期到成年期更严重的ADHD症状和外化行为以及家庭、教育和职业损害可靠相关。我们还对ADHD行为遗传学研究中使用的合适内表型提出了相反观点。