In the AA sample, the top signals were also in genes potentially involved in signal transduction, suggesting the importance of signaling pathways to alcohol use disorders. Similar to the results in the EA sample, the AA sample produced significant gene-wise results in a gene encoding a potassium voltage gated channel protein. In the EA sample, the signal was in KCNMA1 and in the AA sample, we observed gene-wise empirical results with KCNQ5, which produced an empirical p=0.0002; indeed, the gene also demonstrates experiment-wide significance. As a member of the Kv7 family of potassium channel subunits, it encodes a protein which functions as a low-threshold voltage gated channel known as M-channel (Brown and Passmore 2009). M-channels are characteristically inhibited by the activity of hormones and transmitters on G-protein coupled receptors. Modulation of ligand-gated ion channels is critical to producing alcohol-induced effects and a recent study looking specifically at channel currents in the mesolimbic dopamine pathway showed that alcohol produced an inhibition of the M-current in ventral tegmental area (VTA), subsequently producing excitation of the dopamine neurons (Koyama, Brodie, and Appel 2007). This is a critical mechanism underlying alcohol-induced increase in dopamine levels in the VTA.
