Tan Hao-Yang, Callicott Joseph H, Weinberger Daniel R
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD 20892, USA.
Cogn Neuropsychiatry. 2009;14(4-5):277-98. doi: 10.1080/13546800903091665.
Schizophrenia has complex genetic heritability. It is also genetically heterogeneous. To the extent that genes are associated with symptom constellations in schizophrenia, they do so by affecting the development and function of neural systems that mediate the expression of such diverse behavioral, cognitive and perceptual phenomena. The genetic mechanisms of human brain dysfunction remain to be well understood. "Imaging genetics" is an emerging field that attempts to integrate the basic biology of putative disease mechanisms with physiological correlates from the live human brain. Here, we review recent imaging genetics work on prefrontal brain systems associated with working memory and executive function - heritable traits relevant to schizophrenia. Starting with genetic variation in dopaminergic systems (e.g., COMT), we examined the modulation of prefrontal brain networks during active cognitive processing; there is also evidence that variation in the expression of dopamine-related downstream intra-cellular signaling molecules (e.g., AKT1) are implicated. Moreover, these genetic variants evidence epistasis on neuroimaging measures, lending further support to the conceptualization that non-additive combinations of multiple genes modulate active human cognitive brain mechanisms. The imaging genetics platform therefore could extend understanding of genetic mechanisms of human cognitive brain processes relevant to neuropsychiatric disease.
精神分裂症具有复杂的遗传遗传性。它在遗传上也是异质性的。就基因与精神分裂症的症状群相关而言，它们是通过影响介导这些多样的行为、认知和感知现象表达的神经系统的发育和功能来实现的。人类大脑功能障碍的遗传机制仍有待深入了解。“影像遗传学”是一个新兴领域，它试图将假定疾病机制的基础生物学与来自活体人类大脑的生理关联整合起来。在此，我们综述了近期关于与工作记忆和执行功能相关的前额叶脑系统的影像遗传学研究工作——这些遗传性状与精神分裂症相关。从多巴胺能系统的基因变异（如儿茶酚-O-甲基转移酶基因）开始，我们研究了在主动认知加工过程中前额叶脑网络的调节；也有证据表明多巴胺相关的下游细胞内信号分子（如蛋白激酶B1）的表达变异与之有关。此外，这些基因变异在神经影像测量上显示出上位效应，进一步支持了多个基因的非加性组合调节人类主动认知脑机制的概念。因此，影像遗传学平台可以扩展对与神经精神疾病相关的人类认知脑过程遗传机制的理解。
