Effect of environmental factors on gene alterations in complex diseases: simulation study using Gene-Environment iNteraction Simulator 2

Background The gene alterations and etiological pathway of complex diseases such as cancer, Down-syndrome, obesity, etc is highly affected with the interactions between genes and environmental factors. To handle a wide variety of complex situations (such as genes and environmental factors) including certain interactions between variables is poorly investigated, in particular if continuous variables will be involved. Simulations with realistic data sets with geneenvironment interactions and gene- gene interactions which affect the risk of a complex disease are a convenient and useful way to characterize the validity of statisticalmodels. In a previous work [1], we have examined the interaction between one gene and one environmental factor as a function of time. In the present study, the geneenvironment iNteraction simulator (GENS2) has been used to simulate interactions through two genetic and one environmental factor which permit, also, for study the same effect on epistatic interactions. Materials and methods We have simulated interactions among two genetic and one environmental factor using the Gene-Environment iNteraction Simulator 2 (GENS2). It is released under the general public license version3.0 [2].This software generates data which allows for epistatic interactions; it imposes no limitations either on how many simulatedindividuals or on number of factors (environmental/ genetic) which should be taken into consideration. Also, we present a mathematical- model to examine the case of two possibly interaction disease predisposing loci. Only one environmental factor has been chosen to interact with two disease predisposing loci with the assumption that: 1- the genetic loci are assumed to have insensitive effects, i.e. no epistasis and they can easily interact following an epistatic way. 2- The disease risk is highly affected with the genetic alterations (either directly- in linear manner or by modifying the effect of the environment). 3- Also, the disease predisposing is not in linkage disorder.