The ubiquitous nature of epistasis in determining susceptibility to common human diseases
The ubiquitous nature of epistasis in determining susceptibility to common human diseases
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DOI：
10.1159/000073735
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发表时间：
2003-01-01
期刊：
影响因子：
1.8
通讯作者：
Moore, JH
中科院分区：
文献类型：
--
作者：
Moore, JH
越来越多的人意识到，上位性或基因-基因相互作用在人类常见疾病的易感性中起着作用。在这篇文章中，我们提出了一个工作假设，即上位性是人类常见疾病遗传结构中普遍存在的组成部分，复杂的相互作用比任何一个易感基因的独立主效应更重要。这一工作假说是基于几个证据的。首先，上位性很重要的观点并不新鲜。事实上，人们认识到孟德尔比率的偏离是由于基因之间的相互作用，这一认识已经存在了近100年。其次，生物分子相互作用在基因调控和生化代谢系统中的普遍存在表明，DNA序列变异与临床终点之间的关系可能涉及基因-基因相互作用。第三，单一多态研究的阳性结果通常不会在独立样本中复制。这对于关联研究和关联研究都是正确的。第四，如果研究得当，通常会发现基因与基因之间的相互作用。我们回顾了其中的每一个点，然后回顾了一种称为多因素降维的分析策略，用于检测上位性。最后，我们提出了一些想法，即如何利用生化系统模型从统计证据中产生关于生物上位性的假设。如果这一工作假说是正确的，这表明我们需要一种研究策略来识别常见的疾病易感基因，这种基因包含而不是忽略了基因与表型关系的复杂性。版权所有(C)2003 S.Karger AG，巴塞尔。
There is increasing awareness that epistasis or gene-gene interaction plays a role in susceptibility to common human diseases. In this paper, we formulate a working hypothesis that epistasis is a ubiquitous component of the genetic architecture of common human diseases and that complex interactions are more important than the independent main effects of any one susceptibility gene. This working hypothesis is based on several bodies of evidence. First, the idea that epistasis is important is not new. In fact, the recognition that deviations from Mendelian ratios are due to interactions between genes has been around for nearly 100 years. Second, the ubiquity of biomolecular interactions in gene regulation and biochemical and metabolic systems suggest that relationship between DNA sequence variations and clinical endpoints is likely to involve gene-gene interactions. Third, positive results from studies of single polymorphisms typically do not replicate across independent samples. This is true for both linkage and association studies. Fourth, gene-gene interactions are commonly found when properly investigated. We review each of these points and then review an analytical strategy called multifactor dimensionality reduction for detecting epistasis. We end with ideas of how hypotheses about biological epistasis can be generated from statistical evidence using biochemical systems models. If this working hypothesis is true, it suggests that we need a research strategy for identifying common disease susceptibility genes that embraces, rather than ignores, the complexity of the genotype to phenotype relationship. Copyright (C) 2003 S. Karger AG, Basel.