Papaleo F, Burdick M C, Callicott J H, Weinberger D R
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Department of Scienze del Farmaco, Universita' degli Studi di Padova, Padova, Italy [3] Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA.
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA.
Mol Psychiatry. 2014 Mar;19(3):311-6. doi: 10.1038/mp.2013.133. Epub 2013 Oct 22.
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.
认知功能具有高度遗传性，复杂基因相互作用的影响尽管无疑很重要，但却很少得到研究。在此，我们在动物模型和人类神经影像学实验中表明，两个基因——儿茶酚-O-甲基转移酶（COMT）和失调素（dys；肌萎缩蛋白结合蛋白1，DTNBP1）——之间存在一致的非线性相互作用，这两个基因通过不同机制参与皮质多巴胺信号传导和前额叶认知功能。在小鼠中，我们发现单独降低COMT或DTNBP1表达的单个基因突变会产生工作记忆优势，而形成鲜明对比的是，在同一只小鼠中同时降低这两个基因的表达则会导致工作记忆缺陷。我们在人类前额叶皮质功能中发现了相同非线性基因相互作用的证据。在一项工作记忆范式中接受功能磁共振成像研究的健康志愿者（N = 176）中，携带降低COMT酶活性的COMT rs4680 Met等位基因纯合子个体表现出相对更有效的前额叶参与。相比之下，我们发现相同基因型在与DTNBP1表达降低相关的dys单倍型背景下效率较低。这些结果表明，上位性在功能上可以是多向性和非线性的，并且在一种上位性背景下假定有益的等位基因在另一种背景下则是相对有害的。这些数据对复杂性状的单基因座关联分析也具有重要意义。
