rs16969968 is a nonsynonymous SNP in the CHRNA5 gene that replaces an aspartic acid with an asparagine at codon 398 of the protein. It is highly conserved across species and the presence of this variant in the α5 receptor subunit has been shown to reduce receptor response to nicotine in in vitro studies (21). This subunit is highly expressed in several areas of the brain, including the ventral tegmental area (22) where nicotine interacts with AChRs. Mice in which α5 expression has been knocked out show greatly reduced sensitivity to nicotine-induced behaviors and seizures (23). However, the consequences of the α5 knockout are not as dramatic as those caused by the loss of other nicotinic receptor subunits (24), resulting in most investigation of AChRs focusing on other subunits. Our convincing findings implicating the α5 receptor subunit and the rs16969968 SNP in smoking behavior argue strongly for investigation into how the reduced activity of this receptor influences downstream consequences of nicotine exposure. Such research may lead to the development of pharmacologic agents that could eliminate the consequences of this amino acid replacement and aid in smoking cessation.
