Of particular interest is the result in KCNMA1 which produced numerous SNPs with p<10-4 and an empirical p=0.016; experimental evidence suggests that this gene may affect development of tolerance to alcohol (Davies et al. 2003; Ghezzi et al. 2004; Pietrzykowski et al. 2004). KCNMA1 encodes the pore-forming alpha 1 subunit of the large conductance, voltage and calcium-sensitive potassium channels, known as BK (for ‘big’ potassium channels) channels. Alcohol has an immediate effect on the BK channel, leading to increased activity (Dopico et al. 1999; Dopico, Anantharam, and Treistman 1998). Some of the actions of alcohol may arise through prolongation of the opening of this channel (Dopico et al. 1999). Experiments involving slo-1, the nematode homolog of KCNMA1, showed that mutant animals were resistant to the effects of alcohol, suggesting that the gene may be involved in alcohol tolerance (Crowder 2004; Davies et al. 2003). KCNMA1 may have a similar effect in humans; polymorphisms in KCNMA1 were associated with the subjective assessment of level of response to alcohol (Schuckit et al. 2005). Given this prior evidence, our findings provide additional evidence that the gene may impact on AD risk.
