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Int. J. Environ. Res. Public Health 2017, 14(10), 1134; https://doi.org/10.3390/ijerph14101134

An Efficient Test for Gene-Environment Interaction in Generalized Linear Mixed Models with Family Data

1
School of Statistics, National University of Colombia, Medellín, Antioquia 050022, Colombia
2
Departament of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
Received: 19 August 2017 / Revised: 20 September 2017 / Accepted: 25 September 2017 / Published: 27 September 2017
(This article belongs to the Special Issue Gene-Environment Interactions and Disease)
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Abstract

Gene-environment (GE) interaction has important implications in the etiology of complex diseases that are caused by a combination of genetic factors and environment variables. Several authors have developed GE analysis in the context of independent subjects or longitudinal data using a gene-set. In this paper, we propose to analyze GE interaction for discrete and continuous phenotypes in family studies by incorporating the relatedness among the relatives for each family into a generalized linear mixed model (GLMM) and by using a gene-based variance component test. In addition, we deal with collinearity problems arising from linkage disequilibrium among single nucleotide polymorphisms (SNPs) by considering their coefficients as random effects under the null model estimation. We show that the best linear unbiased predictor (BLUP) of such random effects in the GLMM is equivalent to the ridge regression estimator. This equivalence provides a simple method to estimate the ridge penalty parameter in comparison to other computationally-demanding estimation approaches based on cross-validation schemes. We evaluated the proposed test using simulation studies and applied it to real data from the Baependi Heart Study consisting of 76 families. Using our approach, we identified an interaction between BMI and the Peroxisome Proliferator Activated Receptor Gamma (PPARG) gene associated with diabetes. View Full-Text
Keywords: gene-environment interaction; generalized linear mixed model; variance component test; score test; ridge regression; best linear unbiased predictor; family data gene-environment interaction; generalized linear mixed model; variance component test; score test; ridge regression; best linear unbiased predictor; family data
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Mazo Lopera, M.A.; Coombes, B.J.; de Andrade, M. An Efficient Test for Gene-Environment Interaction in Generalized Linear Mixed Models with Family Data. Int. J. Environ. Res. Public Health 2017, 14, 1134.

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