Epidemiological studies have demonstrated that both environmental and genetic factors are associated with different dimensions of smoking behavior [3]. The heritability of smoking quantity is estimated to be between 0.49 and 0.56 [4], and different GWAS have identified and replicated signals within the nicotinic acetylcholine receptor genes on chromosome 15q25 (CHRNA5-A3-B4) [5]–[10] and chromosome 8p11 (CHRNB3-A6) [8], [9], as well as nicotine metabolizing genes on chromosome 19q13 (CYP2A6-B6) [9], [10];. Each of these variants explains 0.5∼1.9% of the phenotypic variance for subjects of European ancestry (EA) [10], [11]. Additional meta-analysis efforts [7] have been carried out to identify more loci, presumably with smaller effect and only detectable by the power gained by a larger number of samples. The most encouraging signals found in a discovery phase, that included more than 15,000 subjects with reported values for smoking quantity, were followed up in a replication phase which encompassed two studies that gathered even larger pools of subjects (ENGAGE [9] n = 46,481; and TAG [10] n = 74,035). However, no additional locus achieved genome-wide significance (p-value<5.0E−8 for 1 million SNPs tested), raising the possibility that structural or rare variants with strong effects explain the missing heritability [12].
