Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia
Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia
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DOI：
10.1073/pnas.111134598
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发表时间：
2001-06-05
影响因子：
11.1
通讯作者：
Weinberger, DR
中科院分区：
文献类型：
--
作者：
Egan, MF;Goldberg, TE;Weinberger, DR
前额叶皮质功能异常是精神分裂症的显著特征，并与遗传风险有关，提示精神分裂症的易感基因可能影响前额叶功能的分子机制。一种潜在的易感性机制涉及调节前额叶多巴胺，它在工作记忆中调节前额叶神经元的反应。我们研究了儿茶酚-O-甲基转移酶(COMT)基因中常见的功能多态(Va(108/158)Met)与前额叶调节的认知和前额叶皮质生理的关系，该基因解释了酶活性和多巴胺分解代谢的4倍变化。在精神分裂症患者、219名正常同胞和55名对照组中，COMT基因与威斯康星执行认知卡片分类测验的成绩呈等位基因剂量相关，可解释持久性错误频率的4%的变异(P=0.001)。与多巴胺增强前额神经功能的其他证据一致，低活性Met等位基因的负载预示着认知能力的增强。然后，我们在三个不同的亚组(n=11-16)的工作记忆任务中研究了COMT基因对前额叶生理学的影响。通过功能磁共振分析，Met等位基因负荷一致地预测了前额叶皮质更有效的生理反应。最后，在对104个三联体进行的基于家庭的关联分析中，我们发现Val等位基因在精神分裂症后代中的传播显著增加。这些数据表明，COMT Val等位基因，因为它增加了前额叶多巴胺的分解代谢，损害了前额叶认知和生理。通过这种机制，精神分裂症的风险略有增加。
Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Va(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups(n = 11-16) assayed with functional MRI, Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology. and by this mechanism slightly increases risk for schizophrenia.