In summary, we presented evidence that the glypican GPC5 participates in human ethanol response, an endophenotype related to AUD risk. The strength of the evidence is derived from the coalescence of results across different experimental systems: mouse linkage identified the candidate locus, human genetic association identified a single gene contained within the mouse-defined locus, and Drosophila behavioral experiments demonstrated that mutant alleles of the gene identified in mice and humans alter the fly’s ethanol response. In addition to our analyses, the literature on GPC5 reports its expression to be spatially and temporally consistent with a putative involvement in ethanol behaviors, and moreover, its expression can be modulated by ethanol. Finally, the known functions of glypicans as modulators of cell signaling systems that participate in neural development as well as synaptic maintenance and plasticity are also consistent with participation in ethanol-induced behaviors. GPC5 is thus a strong candidate as a gene involved in ethanol response and the development of alcohol use disorders.
