GWAS for addictions is at a relatively early stage. Several addictions have yet to be evaluated by GWAS and the samples that have been studied thus far have either not been very large (<10,000), or have been flawed by cross-site or cross-country heterogeneity, less than optimal phenotyping, and an insufficient number of subjects with extreme phenotypes. So far, the strongest, and confirmed, locus detected by GWAS is for the CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.38,98–102 This region harbors a locus-altering propensity to nicotine addiction. Nicotinic acetylcholine receptors (nAChRs) are pentameric cholinergic receptors that form ligand-gated ion channels. They are key mediators of the effect of nicotine on the central nervous system. Neuronal subtypes of nAChRs include various homomeric or heteromeric combinations of 12 different nicotinic subunits: α2 through α10 and β2 through β4. The CHRNA5-CHRNA3-CHRNB4 gene cluster encodes for the α5, α3, and β4 subunits. Association of genetic variation within this region to smoking behavior was initially discovered using a candidate gene approach99,100 but was subsequently replicated by GWAS. GWAS detect a highly significant peak on chromosome 15q25 corresponding to the region where these three genes are located (Fig. 9).
