The strongest association was between a SNP in a nonselective sodium leak channel NALCN and the probability of high-risk membership. This SNP, rs17484734, is in a recombination hotspot (Figure 3A). As a result, only one imputed SNP provided supporting evidence for association. This channel can be activated by several peptides including acetylcholine and substance P, both of which have been shown to interact with alcohol. Acetylcholine is released when alcohol binds to the nicotinic acetylcholine receptors as an agonist (Bito-Onon et al., 2011; Feduccia et al., 2012). Substance P, through interaction with the neurokinin 1 receptor, has been implicated in alcohol consumption, preference, and reinstatement, and is a potential therapeutic target for AD (Schank et al., 2012). One of the components of the NALCN complex is UNC79, the homolog of which was shown to increase alcohol consumption in mice and led to increased sensitivity to alcohol in C. elegans (Speca et al., 2010).
