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Using Genetic Marginal Effects to Study Gene-Environment Interactions with GWAS Data

Abstract

Gene-environment interactions (GxE) play a central role in the theoretical relationship between genetic factors and complex traits. While genome wide GxE studies of human behaviors remain underutilized, in part due to methodological limitations, existing GxE research in model organisms emphasizes the importance of interpreting genetic associations within environmental contexts. In this paper, we present a framework for conducting an analysis of GxE using raw data from genome wide association studies (GWAS) and applying the techniques to analyze gene-by-age interactions for alcohol use frequency. To illustrate the effectiveness of this procedure, we calculate genetic marginal effects from a GxE GWAS analysis for an ordinal measure of alcohol use frequency from the UK Biobank dataset, treating the respondent’s age as the continuous moderating environment. The genetic marginal effects clarify the interpretation of the GxE associations and provide a direct and clear understanding of how the genetic associations vary across age (the environment). To highlight the advantages of our proposed methods for presenting GxE GWAS results, we compare the interpretation of marginal genetic effects with an interpretation that focuses narrowly on the significance of the interaction coefficients. The results imply that the genetic associations with alcohol use frequency vary considerably across ages, a conclusion that may not be obvious from the raw regression or interaction coefficients. GxE GWAS is less powerful than the standard “main effect” GWAS approach, and therefore require larger samples to detect significant moderated associations. Fortunately, the necessary sample sizes for a successful application of GxE GWAS can rely on the existing and on-going development of consortia and large-scale population-based studies.

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Acknowledgement

This work was supported by 5R01AA015416-09 and R01AA018333S1.

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Correspondence to Brad Verhulst.

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Brad Verhulst, Joshua N. Pritikin, James Clifford, and Elizabeth C. Prom-Wormley declare that they have no conflicts of interest related to the publication of this article.

Ethical approval

The data used for the demonstration section of this study were obtained from the UK Biobank (application number 40967) and involved secondary data analysis. As no identifying information was transferred, the data was not deemed “Human Subjects Data”, and appropriate human subjects waivers were obtained by the authors.

Human and animal rights and informed consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The data that were analyzed were completely de-identified, and thus were not considered human subjects data under the NIH regulations. A human subjects exemption for the project was received from Texas A&M University.

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Verhulst, B., Pritikin, J.N., Clifford, J. et al. Using Genetic Marginal Effects to Study Gene-Environment Interactions with GWAS Data. Behav Genet 51, 358–373 (2021). https://doi.org/10.1007/s10519-021-10058-8

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Keywords

  • Gene-environment interaction (GxE)
  • Genome-wide association study (GWAS)
  • Genetic marginal effects
  • Alcohol use frequency