The major hub genes of PFC saline vs ethanol S-score networks, and particularly ErGeN3, included a number of genes previously implicated in drug dependence and neurological disease. The aforementioned node with the highest betweenness centrality in ErGeN3 was a probe-set targeting Grm3. It is well established that metabotropic glutamate receptors play an important functional role in the development of AUD [75], [52], [76]. Studies have demonstrated, in particular, that modulation of Grm3 decreases ethanol seeking in rats [77], [78]; although the agonists used in these studies also bind Grm2. Grm3 is also a high priority candidate gene for schizophrenia, as a group II mGluR agonist (LY354740) blocked many symptoms induced in the rat phencyclidine treatment model of schizophrenia [79]. Grm3 has also been associated with schizophrenia phenotypes in human genome-wide association (GWA) studies [80]. Among the genes adjacent to Grm3 in ErGeN3, the strongest correlation was between Grm3 and Nrg3 (r = 0.97, p-value<1e-16). Like Grm3, Nrg3 (neuregulin 3) is a highly connected gene in ErGeN3 as well as a schizophrenia candidate gene [81], [82].
