KCNMA1 encodes the calcium activated large conductance (BK) potassium channel, alpha1 subunit. BK channels are direct molecular targets of ethanol (Dopico et al., 2016), underlie a molecular mechanism of cellular tolerance to alcohol (Bettinger and Davies, 2014), and play a key role in alcohol withdrawal related phenotypes (Ghezzi et al., 2014; N'Gouemo and Morad, 2014; Kreifeldt et al., 2013; Kreifeldt et al., 2015). Along with evidence from Edenberg et al., 2010 who reported a similar association between SNPs within KCNMA1 and alcohol dependence in both European and African American samples, KCNMA1 represents a compelling candidate gene requiring further analysis. In particular, because there is direct molecular evidence implicating the BK channel as an alcohol-responsive protein, it will be interesting to determine how the specific SNPs identified in the alcohol dependence GWAS change the function of the channel in vitro and in vivo (see Table 3). For example, humanized mice could be generated that express the human variant of the BK channel associated with alcohol dependence and these transgenic mice could be tested for various alcohol-related behaviors such as withdrawal-induced drinking.
