Nicotine is the primary addictive component of tobacco products, and its physiological effects are mediated through neuronal nicotinic acetylcholine receptors.1 The α5/α3/β4 nicotinic receptor subunit gene cluster on chromosome 15 harbors the strongest and most replicated genetic risk factor for smoking-related traits. Many independent studies demonstrated that rs16969968, a common coding variant (D398N) in the α5 nicotinic receptor subunit gene (CHRNA5), is associated with nicotine dependence, heaviness of smoking, and smoking cessation, as well as smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease.2-10 Subsequent large-scale meta-analyses of European ancestry populations identified rs16969968 as unequivocally associated with heaviness of smoking (p=5.57×10−72).11-13 Recently, rs16969968 was shown to have a similar effect in African ancestry populations,14,15 where the minor allele is less common. Beyond these robust association studies across ancestry groups, functional studies support the biological role of CHRNA5 and rs16969968 in the development of nicotine dependence.4,16
