Pathway analyses indicated several intuitive biological mechanisms. Top results for mean adolescent consumption (“neuronal system” and “transmission across chemical synapses”) suggested extensive involvement of GABAergic (e.g., SLC6A1, GABRG3, GABRG2, GABBR2) and glutamatergic (e.g., GRIK5, GLUL, GRIK1, GRIN2B) neurotransmission. Given that GABA and glutamate neurotransmitter systems are primary pharmacodynamic targets of alcohol (for review see Vengeliene et al., 2008), these results are consistent with extant knowledge of the drug’s biological mechanisms. “Celecoxib pharmacodynamics” and “nuclear hormone receptors” also offer intriguing biological mechanisms for genetic variation in alcohol metabolism. Celecoxib acts by inhibiting prostaglandin synthesis (Penning et al., 1997). Prostaglandins are lipid autocrine/paracrine mediators with a variety of physiological effects, including inflammation modulation (Hata & Breyer, 2004), which have been shown to moderate alcohol “hangover” intensity (Wiese, Shlipak & Browner, 2000) and reduce alcohol-induced liver toxicity (Nanji et al., 1993). “Nuclear hormone receptors” (NHR) are intracellular proteins responsible for sensing steroid and thyroid hormones and some other signaling molecules. Multiple NHR genes implicated in the current analysis are specifically expressed in liver (e.g., HNF4A, HNF4G) and several others function as thyroid hormone
