Inference of Cross-Level Interaction between Genes and Contextual Factors in a Matched Case-Control Metabolic Syndrome Study: A Bayesian Approach

Shi-Heng Wang,Pi-Hua Liu,Lee-Ming Chuang,Po-Chang Hsiao,Chuhsing K Hsiao,Wei J Chen,Giuseppe Novelli

doi:10.1371/journal.pone.0056693

Shi-Heng Wang, Pi-Hua Liu + Show 5 more

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https://doi.org/10.1371/journal.pone.0056693

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Abstract

Genes, environment, and the interaction between them are each known to play an important role in the risk for developing complex diseases such as metabolic syndrome. For environmental factors, most studies focused on the measurements observed at the individual level, and therefore can only consider the gene-environment interaction at the same individual scale. Indeed the group-level (called contextual) environmental variables, such as community factors and the degree of local area development, may modify the genetic effect as well. To examine such cross-level interaction between genes and contextual factors, a flexible statistical model quantifying the variability of the genetic effects across different categories of the contextual variable is in need. With a Bayesian generalized linear mixed-effects model with an unconditional likelihood, we investigate whether the individual genetic effect is modified by the group-level residential environment factor in a matched case-control metabolic syndrome study. Such cross-level interaction is evaluated by examining the heterogeneity in allelic effects under various contextual categories, based on posterior samples from Markov chain Monte Carlo methods. The Bayesian analysis indicates that the effect of rs1801282 on metabolic syndrome development is modified by the contextual environmental factor. That is, even among individuals with the same genetic component of PPARG_Pro12Ala, living in a residential area with low availability of exercise facilities may result in higher risk. The modification of the group-level environment factors on the individual genetic attributes can be essential, and this Bayesian model is able to provide a quantitative assessment for such cross-level interaction. The Bayesian inference based on the full likelihood is flexible with any phenotype, and easy to implement computationally. This model has a wide applicability and may help unravel the complexity in development of complex diseases.

Highlights

Both genetic and environmental factors play an important role in the development of many diseases, often interacting in ways that elevate disease risk, especially in complex diseases such as obesity, cardiovascular disease, and psychopathology [1,2,3]
The research reported here was motivated by a matched casecontrol metabolic syndrome study where interest lay in the interaction between genes and contextual variables, as well as SNP-SNP interaction
Such cross-level genetic and environmental (GE) interaction can be as important as the individual level Ge interaction, and its influence should not be overlooked

Summary

Introduction

Both genetic and environmental factors play an important role in the development of many diseases, often interacting in ways that elevate disease risk, especially in complex diseases such as obesity, cardiovascular disease, and psychopathology [1,2,3]. Community disparity in medical resources may affect the availability and quality of treatment, and living in a deprived area may result in a somewhat modified effect on the health risk incurred by individuals who engage in unhealthy behaviors such as smoking [7]. This contextual exposure affects the individual health status of each member of the group, and is called the contextual effect [8,9]. Several research groups adopted Bayesian or non-Bayesian hierarchical models to alleviate the problem of nested variability [10,11], but these models are not for matched case-control studies and not for group-level GE interaction [12,13,14,15]

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