Nicotine is the main psychoactive compound in tobacco, and exerts its functions by binding to nicotinic acetylcholine receptors (nAChR). Genome‐wide association study (GWAS) meta‐analyses have robustly reported that the CHRNA5‐CHRNA3‐CHRNB4 nAChR gene cluster on 15q25 and the CHRNB3‐CHRNA6 region on 8p11.21 are associated with smoking quantity (measured by cigarettes per day, CPD) and nicotine dependence (ND) (measured by the Fagerström Test for Nicotine Dependence, FTND (Heatherton et al. 1991)) (Liu et al. 2010; The Tobacco and Genetics Consortium 2010; Thorgeirsson et al. 2010). However, less than 1% of the variance in the amount smoked is explained by alleles of these genes, with an average effect per allele of one CPD. Age of onset phenotypes have been utilized in some targeted studies of nAChR genes. Variants in the CHRNA5‐CHRNA3‐CHRNB4 gene cluster are shown to predict a later age of smoking cessation (Chen et al. 2012), and the effect of a functional CHRNA5 variant (rs16969968) on smoking quantity is reported to be stronger in early‐onset smokers than in late‐onset smokers (Hartz et al. 2012). Further, a genetic risk score composed of CHRNA5‐CHRNA3‐CHRNB4
