For markers with a p-value <10−3, additional analyses were carried out. These genes are functionally enriched for a number of molecular function categories related to glutamate activity, as well as for categories involving transport activity. In addition, a disproportionate number of these genes fall into the cellular component categories such as cell junction, postsynaptic membrane, ionotropic glutamate receptor complex, and synapse. Overall, these results suggest that genes associated with the comorbid phenotype are involved in neural processes. Specifically, the glutamatergic system is strongly implicated, which is not surprising given its previous association with depression, alcohol dependence (for reviews, see Kohnke, 2008; McNally et al., 2008) and alcohol response (Joslyn et al., 2010). Most of the glutamate-related genes implicated in the current study (GRIN2C, GRIN2A, GRIA1, and GRIA4) have not previously been associated with depression or alcohol dependence, but GRID1 was modestly associated with major depression in a genome-wide meta-analysis (Muglia et al., 2008). In addition, all but GRIN2C have been associated with schizophrenia (Carter, 2007; O'Connor and Hemby, 2007; Treutlein et al., 2009b), and GRIN2A has been implicated in heroin addiction among African Americans (Levran et al., 2009).
