We focused on cholinergic nicotinic receptor subunit genes because the protein products physically combine to form biologically active receptors that bind nicotine. For example, the α4 and α5 nicotinic acetylcholine receptor (nAChR) subunits combine with the nAChR β2 subunit to form an α42β22α51 receptor that is expressed in various brain regions including the mesolimbic reward pathway (McClure-Begley et al. 2009; Salminen et al. 2004; Zoli et al. 2002). Thus, it is plausible that variants in and around the genes that form these subunits may alter the subunit makeup of nicotinic receptors or the relative expression of the receptors. Of course, joint effects for these genes need not be limited to changes that alter an amino acid, but can include variants that alter splicing, mRNA expression, stability, or other regulatory factors. Our analytic evidence of joint effects can suggest models that can be tested biologically in the laboratory.
