Gene-environment dependence creates spurious gene-environment interaction.
Gene-environment dependence creates spurious gene-environment interaction.
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DOI：
10.1016/j.ajhg.2014.07.014
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发表时间：
2014-09-04
影响因子：
9.8
通讯作者：
Fletcher O
中科院分区：
文献类型：
--
作者：
Dudbridge F;Fletcher O
基因-环境相互作用有可能揭示导致疾病的生物过程，并提高流行病学风险模型的准确性。然而，相对较少的这种相互作用尚未得到证实。在某种程度上，这是因为通常研究的是诸如标签snp之类的遗传标记，而不是因果变异本身。先前的研究表明，当基因和环境相互独立时，这会导致大量的功率损失和样本量的增加。然而，基因和环境之间的依赖可以通过多种方式产生，包括介导、多效性和混杂，最近发表了一些基因-环境依赖下基因-环境相互作用的例子。这里我们表明，在基因-环境依赖下，即使因果变异和环境之间没有相互作用，标记和环境之间也可能存在统计上的相互作用。我们给出了没有标记-环境相互作用的简单条件，并注意到当存在基因-环境依赖时，它们通常不成立。此外，基因-环境依赖性适用于因果变异，不能从标记数据进行评估。如果两个因果变异处于连锁不平衡状态，基因-基因相互作用也容易出现同样的问题。除了现有的对机制解释的担忧，我们建议在报告遗传标记的相互作用时进一步谨慎。
Gene-environment interactions have the potential to shed light on biological processes leading to disease and to improve the accuracy of epidemiological risk models. However, relatively few such interactions have yet been confirmed. In part this is because genetic markers such as tag SNPs are usually studied, rather than the causal variants themselves. Previous work has shown that this leads to substantial loss of power and increased sample size when gene and environment are independent. However, dependence between gene and environment can arise in several ways including mediation, pleiotropy, and confounding, and several examples of gene-environment interaction under gene-environment dependence have recently been published. Here we show that under gene-environment dependence, a statistical interaction can be present between a marker and environment even if there is no interaction between the causal variant and the environment. We give simple conditions under which there is no marker-environment interaction and note that they do not hold in general when there is gene-environment dependence. Furthermore, the gene-environment dependence applies to the causal variant and cannot be assessed from marker data. Gene-gene interactions are susceptible to the same problem if two causal variants are in linkage disequilibrium. In addition to existing concerns about mechanistic interpretations, we suggest further caution in reporting interactions for genetic markers.
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