Another aspect of missing heritability in alcohol GWAS is the layers of interactions between genes within the context of the rest of the genome and the environment in which they exist. This non-linear combination of genes/gene-products is referred to as epistasis. Because AD is a complex developmental disease that involves impaired neural development and function, it is undoubtedly fraught with molecular interactions (i.e., DNA and proteins) that are difficult to model statistically. For example, Palmer et al. (2003) suggested that the background of a knockout mouse might be important when studying response to ethanol. In their study of two different DRD2 knockout mouse strains, the authors showed that the effects of the null allele on ethanol’s stimulant and sensitizing effects differed based on the background used to develop the knockout strain (Palmer et al., 2003). So far, there has been modest evidence of statistical epistatic effects on AD in the human literature, possibly because of a lack of power in most studies. In a recent study, Kumar et al. discovered epistatic effects between the mu and kappa opioid system, with
