Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD 20892, USA.
Mol Psychiatry. 2012 Oct;17(10):1007-16. doi: 10.1038/mp.2011.91. Epub 2011 Jul 26.
AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients.
AKT1 控制着内侧颞叶（MTL）发育和可塑性的重要过程，但人类 AKT1 基因变异对健康或疾病状态下这些过程的影响尚不清楚。在这里，我们报告称，先前与 AKT1 蛋白表达、前额叶功能和精神分裂症相关的 AKT1 变体（rs1130233）会影响人类 MTL 结构和记忆功能。此外，支持 AKT1 在传递海马神经可塑性和多巴胺能过程中的作用，我们发现了与 BDNF 和 COMT 中的功能多态性的上位性，这些基因也与 AKT1 相关的 MTL 生物学有关。与先前的预测一致，即这些生物学过程与精神分裂症有关，我们发现了相同的 AKT1、BDNF 和 COMT 功能变体与精神分裂症风险之间的上位性，以及 AKT1 与在普通临床应用中激活 AKT1 的认知和大脑体积测量的效应之间的药物遗传学相互作用——锂和丙戊酸钠。我们的研究结果表明，AKT1 至少部分通过与大脑神经可塑性和发育相关的特定遗传相互作用，影响精神分裂症和伴随的认知缺陷的风险，并且这些 AKT1 效应可能在患者中通过药理学调节。
