Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans.
Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans.
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DOI：
10.1038/mp.2013.133
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发表时间：
2014-03
影响因子：
11
通讯作者：
Weinberger DR
中科院分区：
文献类型：
--
作者：
Papaleo F;Burdick MC;Callicott JH;Weinberger DR
认知功能是高度遗传的，复杂的遗传相互作用的影响，虽然无疑是重要的，但很少受到调查。在这里，我们在动物模型和人类神经影像学实验中显示了两个基因-儿茶酚-O-甲基转移酶（COMT）和dysbindin（dys;肌养蛋白结合蛋白1（DTNBP 1））之间一致的非线性相互作用-通过不同的机制在皮质多巴胺信号传导和前额叶认知功能。在小鼠中，我们发现单一基因突变降低COMT或DTNBP 1的表达单独产生工作记忆优势，而与此形成鲜明对比的是，同一小鼠中两者的基因减少产生工作记忆缺陷。我们在人类的前额叶皮质功能中发现了同样的非线性遗传相互作用的证据。在健康志愿者（N = 176）的研究与功能磁共振成像在工作记忆的范例，个体纯合子的COMT rs 4680 Met等位基因，降低COMT酶活性表现出相对更有效的前额参与。与此相反，我们发现，相同的基因型是低效率的dys单倍型与DTNBP 1表达减少的背景。这些结果说明上位性在功能上可以是多方向的和非线性的，并且在一个上位性背景中的有益等位基因在另一个上位性背景中是相对有害的。这些数据也有重要的影响，复杂性状的单位点关联分析。
Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes—catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))—implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N = 176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits.