Alcohol use disorders are influenced by many interacting genetic and environmental factors. Highlighting this complexity is the observation that large genome-wide association experiments have implicated many genes with weak statistical support. Experimental model systems, cell culture and animal, have identified many genes and pathways involved in ethanol response, but their applicability to the development of alcohol use disorders in humans is undetermined. To overcome the limitations of any single experimental system, the analytical strategy used here was to identify genes that exert common phenotypic effects across multiple experimental systems. Specifically, we (1) performed a mouse linkage analysis to identify quantitative trait loci that influence ethanol-induced ataxia; (2) performed a human genetic association analysis of the mouse-identified loci against ethanol-induced body sway, a phenotype that is not only comparable to the mouse ethanol-ataxia phenotype but is also a genetically influenced endophenotype of alcohol use disorders; (3) performed behavioral genetic experiments in Drosophila showing that fly homologs of GPC5, the member of the glypican gene family implicated by both the human and mouse genetic analyses, influence the fly's response to ethanol; and (4) discovered data from the literature demonstrating that the genetically implicated gene's expression is not only temporally and spatially consistent with involvement in ethanol-induced behaviors but is also modulated by ethanol. The convergence of these data provides strong support to the hypothesis that GPC5 is involved in cellular and organismal ethanol response and the etiology of alcohol use disorders in humans.

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.