Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution.
Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution.
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DOI：
10.1016/j.biopsych.2013.09.006
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发表时间：
2014-01-01
影响因子：
10.6
通讯作者：
Keller, Matthew C.
中科院分区：
文献类型：
--
作者：
Keller, Matthew C.
关键词：
候选基因-环境(G×E)交互作用研究检验了这样一种假设，即某些环境变量(例如，童年虐待)对某些结果指标(例如，抑郁症)的影响取决于特定的基因多态。由于这项研究本质上是非实验性的，研究人员理所当然地担心，检测到的互动可能是由混杂因素(例如种族、性别、年龄、社会经济地位等)驱动的。而不是通过特定的遗传或环境变量本身。为了消除对检测到的G×E相互作用的这种替代解释，研究人员通常将潜在的混杂因素作为协变量输入一般的线性模型。然而，这种做法并不能控制这些变量可能对G×E交互作用产生的影响。相反，为了正确控制混杂因素，研究人员需要在测试G×E项的同一模型中输入逐个环境的协变量和逐个基因的协变量交互作用项。在这篇手稿中，我解析地论证了这一点，并证明了不适当地控制协变量的做法是迄今为止G×E交互作用文献中的规范。因此，许多研究人员认为已经被排除的G×E发现的替代解释并没有被排除。
Candidate gene-by-environment (G×E) interaction research tests the hypothesis that the effects of some environmental variable (e.g., childhood maltreatment) on some outcome measure (e.g., depression) depend on a particular genetic polymorphism. Because this research is inherently non-experimental, investigators have been rightly concerned that detected interactions could be driven by confounders (e.g., ethnicity, gender, age, socioeconomic status, etc.) rather than by the specified genetic or environmental variables per se. In an attempt to eliminate such alternative explanations for detected G×E interactions, investigators routinely enter the potential confounders as covariates in general linear models. However, this practice does not control for the effects these variables might have on the G×E interaction. Rather, to properly control for confounders, researchers need to enter the covariate-by-environment and the covariate-by-gene interaction terms in the same model that tests the G×E term. In this manuscript, I demonstrate this point analytically and show that the practice of improperly controlling for covariates is the norm in the G×E interaction literature to date. Thus, many alternative explanations for G×E findings that investigators had thought were eliminated have not been.
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