People who start smoking at a young age are more likely to have higher lifetime amounts of tobacco smoked and consequently are at greater risk of becoming nicotine dependent [19]. Variants flanking and within the CHRNA5-CHRNA3-CHRNB4 gene cluster region affect the risk for nicotine dependence [8]–[15], and are also involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence [26]. Studies using haplotype analysis reported that common haplotypes in this gene cluster are associated with nicotine dependence in adults especially among those who began daily smoking before age 16 [21]. These haplotypes also linked to nicotine withdrawal and smoking cessation phenotypes though the associations were not influenced by AAO of daily smoking [27]. In this study, we conducted family-based association tests using AAO of daily smoking as a quantitative phenotype. We identified an association between AAO of daily smoking and a group of correlated variants located upstream of CHRNB4 gene in a cohort of young adults, that was independent of the effect of rs16969968.
