Gene-by-environment interaction studies have not properly controlled for potential confounders: The problem and the (simple) solution

By Matthew C. Keller. Biological Psychiatry, 2013

642 citations recorded by the source corpus.

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.

Subfields: Experimental and Cognitive Psychology, Health, Statistics and Probability

View Paper: https://www.semanticscholar.org/paper/127cc7a78b0ce74260f6f5d08833a5861ed11e34

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In Experimental and Cognitive Psychology

1. Josep Maria Haro
2. Dan J Stein

In Health

1. Josep Maria Haro
2. E. Karam
3. Douglas F. Levinson
4. E. Bromet
5. Dan J Stein
6. K. Demyttenaere

In Statistics and Probability

1. Chi-yi Hu
2. Josep Maria Haro
3. E. Karam
4. Douglas F. Levinson
5. S. Florescu
6. E. Bromet
7. Dan J Stein

Citations in the corpus

• Depression and Anxiety (2008, positive): “Analyses with PRS were also adjusted for three ancestry‐informative principal components, and interaction analyses were additionally adjusted for covariate‐by‐gene and covariate‐by‐exposure interaction terms, as suggested by Keller (2014).”