Background and purpose: Genome-wide analysis of gene-gene interactions has been recognized as a powerful avenue to identify the missing genetic components that can not be detected by using current single-point association analysis.Recently, several model-free methods (e.g.the commonly used information based metrics and several logistic regression-based metrics) were developed for detecting non-linear dependence between genetic loci, but they are potentially at the risk of inflated false positive error, in particular when the main effects at one or both loci are salient.