An early Genome Wide Association Study (GWAS) followed by a Gene Set Enrichment Analysis (GSEA) found that when gene variations were analyzed for grouping, neuronal signaling genes dominated other associations with an individual’s level of response to alcohol and glutamate was the primary neurotransmitter system implicated.181 These authors also noted that FHP individuals show an altered level of response to alcohol and ketamine (an NMDA antagonist), thus confirming a genetic risk for alcoholism and altered glutamatergic function.181,182 Similarly, a pathway analysis of variants in 130 addiction-related candidate genes confirmed a significant role for glutamate signaling in alcohol dependence, with the odds ratio of mGlu1-rs2300620 (>1.6) exceeding that of any other significant gene variant.183 A contemporary study using pathway analysis revealed the NMDA-dependent AMPA-trafficking cascade centered on the gene encoding the multiple PDZ domain protein (Mpdz) was significantly associated with alcohol dependence in a subset of the SAGE study.184
