To provide proof of principle for the potential of this translational approach, the human ortholog of the Drosophila Men gene, which encodes malic enzyme, was targeted as a candidate gene based on artificial selection, mutational and transcriptional profiling studies [86,93,94]. The gene encoding malic enzyme is also differentially expressed in mice upon acute alcohol treatment [95]. Malic enzyme represents a metabolic switch, converting malate into pyruvate while generating NADPH, an essential co-factor for fatty acid biosynthesis (Figure 2). Thus, the malic enzyme reaction enables the development of alcohol-induced fatty liver syndrome. Association studies on the Framingham Offspring cohort showed that intronic SNPs of the gene encoding malic enzyme 1 (ME1) were associated with amount of cocktail drinking, indicating that variation in expression of cytoplasmic malic enzyme contributes to variation in alcohol consumption. Thus, translational approaches from model organisms to humans can identify SNPs that are associated with drinking behavior, with an effect size that could not have been resolved with large-scale unbiased GWASs [92].
