A modest association (p < 10–6) was found in a SNP (rs6483362) in GRM5 which encodes the glutamate metabotropic-5 G-protein coupled receptor (mGlu5) (Fig. 1 and Table 3). mGlu1/5 receptor binding is increased in the hippocampus of type 1 alcoholics (Kupila et al., 2013). mGlu5 receptor antagonists reduce alcohol-withdrawal induced anxiety in rats (Kumar et al., 2013). mGlu5 signaling on striatal Dopamine-D1 receptor expressing neurons is necessary for both novelty-seeking behavior and the abstinence-induced escalation of alcohol drinking in mice (Parkitna et al., 2013). mGlu5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior (Sinclair et al., 2012). Thus, although SNPs in GRM5 did not meet the stringent genome-wide significant threshold in the study by Bierut et al., 2010, results from human alcoholic brain and animal models of alcohol dependence support a key role of GRM5 in alcohol dependence phenotypes and the negative affective state during protracted abstinence.
