Previous genome-wide association studies (GWASs) identified 14 common SNVs [1, 6–12] (with minor allele frequency, MAF >0.01) robustly associated with smoking behaviour-related traits (P < 5 × 10−8). The 15q25 (CHRNA3/5-CHRNB4) region has the largest effect, explaining ~1% and 4–5% of the phenotypic variance of smoking quantity [13] and cotinine, a biomarker of nicotine intake [14], respectively. Overall, genetic loci identified to date explain ~2% of the estimated genetic heritability of smoking behaviour [6], which is reported to be between 40–60% [15–17]. A recent study suggested that an important proportion (~3.3%) of the phenotypic variance of smoking behaviour-related traits was explained by rare nonsynonymous variants (MAF <0.01) [18]. Hence, well-powered studies of rare variants are needed.
