Three replicated loci have some biologically plausible interpretation supported by previous studies. First, consider FERM domain containing 4A (FRMD4A), which is homologous in mouse EpH4 epithelial cells. This gene encodes a scaffolding protein controlling the activation of Arf6 by connecting Par-3, the Arf6 guanine-nucleotide exchange factor (GEF), and cytohesin-1 (Ikenouchi and Umeda 2010). Previously, a hypermethylation event was detected in FRMD4A in an analysis of DNA methylation of benzopyrene (BaP)-treated MCF-7 cells (Sadikovic et al. 2007). BaP is a common polycyclic aromatic hydrocarbon, an important class of environmental contaminants, that is also present in cigarette smoke. Moreover, Johnson et al. (2008) reported that FRMD4A was associated with substance dependence phenotypes defined by Diagnostic and Statistical Manual (DSM) diagnoses of substance abuse and FTND diagnoses of ND. FRMD4A is responsible for variation of the electrocardiographic RR interval (Marroni et al. 2009).
