Genes showing significant differences in expression between alcohol-dependent subjects and controls were enriched in pathways related to interferon and GADD45 signaling (Fig. 1b). Interferons are cytokines that have antiviral, antiproliferative, and immunomodulatory effects and the interferon pathway plays a critical role in human innate and adaptive immune responses34. Our pathway analysis results are consistent with earlier findings showing induction of innate immune genes by stress and drug abuse35. Furthermore, mRNA expression studies in human brain showed significant changes in expression of genes related to immune or inflammatory responses in hippocampus7 and nucleus accumbens8. The neuroinflammation associated with chronic alcohol exposure and withdrawal may be attributed to microglial activation and is associated with the neuropathology of chronic alcohol exposure36. Differentially expressed genes (FDR < 25%) also mapped to networks associated with neurodegenerative disorders and organismal injury (Fig. 1d). Many differentially expressed genes in this network are involved in nervous system development and function. Specifically TRPC3 and calcium dependent protein kinase 4 (CAMK4) are involved in excitatory post-synaptic current while Ampa receptor, Glutamate Ionotropic receptor AMPA type subunit 4 (GRIA4), Calcium dependent protein kinase ii (CaMKII) and CAMK4 are involved in synaptic transmission.
