The strongest genetic signal for tobacco-use phenotypes identified via GWAS is located in a gene cluster on chromosome 15 containing the CHRNA5, CHRNA3, and CHRNB4 genes (CHRNA5-A3-B4), which encode the alpha-5, alpha-3, and beta-4 nicotinic acetylcholine receptor subunits, respectively. Each additional copy of the minor risk allele at this locus is associated with one extra cigarette smoked per day. The locus [11] accounts for approximately 1% of the variation in cigarette consumption in daily smokers [12] and approximately 4% of the variation in cotinine levels, the primary metabolite of nicotine and a more precise biomarker of exposure [13]. The same locus has been identified in GWAS of lung cancer [11,14], peripheral arterial disease [11], and chronic obstructive pulmonary disease [15]. One parsimonious interpretation of these results is that these are all diseases for which cigarette smoking is a strong, causal risk factor. Indeed, the effect of smoking on these outcomes is sufficiently strong that variants associated with heaviness of smoking achieve genome-wide significance even in unstratified GWAS (i.e., where smokers and never-smokers are not considered separately). When stratified, one should
