Although the majority of the studies of CHRNA5/ CHRNA3/CHRNB4 variation and tobacco have targeted smoking behaviors in adulthood, a few reports specifically focused on early smoking behaviors. Weiss et al. found that a CHRNA5/CHRNA3/CHRNB4 haplotype including SNPs rs16969968 and rs578776 was significantly associated with severity of nicotine dependence among individuals who began daily smoking at or before age 16, but not in those who began smoking after age 16 [Weiss et al., 2008]. Correlated SNPs rs1948 (CHRNB4) and rs8023462 (CHRNA3/CHRNB4) (r2 = 0.8) were found to be associated with early age of tobacco initiation in two independent samples [Schlaepfer et al., 2008]. These two SNPs are not in high linkage disequilibrium with any of the four loci mentioned above (rs1696998 r2 = 0.32, rs578776 r2 = 0.09, rs588765 r2 = 0.56, and rs12914008 r2 = 0.02) (1000 Genomes Pilot) 1 CEU [Abecasis et al., 2012]. A second study targeting age of tobacco initiation in a Korean sample found that SNPs rs6495308, rs11072768, and rs951266 were significant for association [Li et al., 2010], but it is not clear whether in this
