Langley Kate, Heron Jon, O'Donovan Michael C, Owen Michael J, Thapar Anita
Department of Psychological Medicine and Neurology, Cardiff University, Wales, England.
Arch Gen Psychiatry. 2010 Dec;67(12):1317-23. doi: 10.1001/archgenpsychiatry.2010.163.
As genes associated with common disorders are increasingly identified, we need to progress from observing associations to identifying risk pathways. The high-activity COMT genotype, in the presence of attention-deficit/hyperactivity disorder (ADHD), has previously been shown to be associated with extreme antisocial behavior. The same genotype has also been implicated in affecting cognitive function in healthy individuals. Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome.
To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether (1) impaired executive control or (2) impaired social understanding act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior.
Prospective epidemiological cohort sample.
The Avon Longitudinal Study of Parents and Children.
Four thousand three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype, ADHD symptoms and diagnoses, and measures of social cognition/understanding and executive control.
Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms.
We replicated the association of the high-activity COMT genotype, in the presence of ADHD, with extreme antisocial behavior (odds ratio, 2.82; 95% confidence interval, 2.02-3.94; P < .001 for the most severe antisocial behavior). The high-activity COMT genotype was associated with both executive control and impaired social understanding. The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social understanding was included (odds ratio, 1.87; 95% confidence interval, 1.26-2.76; P = .002).
The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.
随着与常见疾病相关的基因越来越多地被识别出来，我们需要从观察关联进展到识别风险途径。先前已表明，在患有注意力缺陷多动障碍（ADHD）的情况下，高活性儿茶酚-O-甲基转移酶（COMT）基因型与极端反社会行为有关。相同的基因型也被认为会影响健康个体的认知功能。因此，认知功能受损可能处于从基因型到临床结果的风险途径上。
在ADHD中复制COMT基因型与反社会行为之间的关联，然后测试（1）执行控制受损或（2）社会理解受损是否作为这种关联的中间表型，并处于COMT基因型与反社会行为之间的风险途径上。
前瞻性流行病学队列样本。
埃文亲子纵向研究。
4365名儿童，他们有关于COMT Val¹⁵⁸Met基因型、ADHD症状和诊断以及社会认知/理解和执行控制测量的数据。
使用《精神疾病诊断与统计手册》第四版（DSM-IV）品行障碍症状评估7.5岁时的反社会行为。
我们在患有ADHD的情况下复制了高活性COMT基因型与极端反社会行为之间的关联（优势比，2.82；95%置信区间，2.02 - 3.94；最严重反社会行为的P <.001）。高活性COMT基因型与执行控制受损和社会理解受损均有关联。在模型中纳入执行控制后，基因型与反社会行为之间的关联强度未变，但纳入社会理解受损后则下降（优势比，1.87；95%置信区间，1.26 - 2.76；P =.002）。
ADHD中的高活性COMT基因型部分通过社会理解受损与反社会行为相关。执行控制受损也与高活性COMT基因型有关，但可能不处于反社会行为的风险途径上。这些发现证明了在同一样本中测试基因型、中间表型和临床结果之间的联系以识别潜在风险途径的重要性。
