Division of Psychosis Studies, Institute of Psychiatry, King's Health Partners, King's College London, London, UK.
Genes Brain Behav. 2011 Apr;10(3):276-85. doi: 10.1111/j.1601-183X.2010.00665.x. Epub 2010 Dec 16.
The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.
精神分裂症-1（DISC1）基因的连锁和遗传关联研究提示其与精神分裂症和双相障碍均有关联。前额皮质功能改变是这两种疾病的一种病理生理学特征，我们最近发现 DISC1 的变异可调节健康志愿者的前额皮质激活。我们的目标是研究 DISC1 多态性 Cys704Ser 对精神分裂症和双相障碍患者前额叶功能的影响。2004 年至 2008 年，我们使用功能磁共振成像研究了精神分裂症患者（N=44）、双相障碍患者（N=35）和健康志愿者（N=53），并在他们执行言语流畅性任务时进行了研究。我们将 Cys704 携带者与 Ser704 纯合子进行了比较，以研究 Cys704Ser 对皮质激活的影响。与我们之前在健康受试者中发现的对前额叶激活的显著影响不同，在精神分裂症或双相障碍组中，在这个或任何其他区域都没有检测到 Cys704Ser 的显著影响。当将对照组与精神分裂症患者进行比较时，左侧中/额上回出现诊断与基因型的相互作用[总体错误率（FWE）P=0.002]。在这个区域，Ser704/ser704 对照组的激活程度高于 Cys704 携带者，而精神分裂症患者则呈现相反的趋势。与在健康受试者中的作用不同，DISC1 Cys704Ser704 基因型的变异与精神分裂症或双相障碍患者前额叶激活的改变无关。在患者中没有发现效应，可能反映了 DISC1 基因型的影响与这些疾病相关的其他基因的影响之间的相互作用，以及/或与疾病对大脑功能的影响之间的相互作用。
