Our association results together with the correlation patterns of these three loci suggest that future haplotype or diplotype analyses across large datasets could clarify the relative contributions of these loci. Our evidence that multiple distinct genetic loci affect smoking quantity is consistent with previous reports of risk and protective haplotypes for nicotine dependence in the Utah and LHS samples [7], and in the COGEND and CPS-II-CPD samples [22]. The Utah/LHS study haplotype included 5 SNPs: two that represent locus 1 (rs16969968 and rs1051730), two that represent locus 2 (rs569207 and rs578776), and one that represents locus 3 (rs680244). The COGEND and CPS-II-CPD haplotype analyses included up to 3 loci, one each for locus 1, 2 and 3. Across all these published studies, the high-risk haplotype carries the risk allele at rs16969968 (locus 1); because of the high |D'| between loci, only one haplotype carries that allele. Among the remaining haplotypes, a low risk haplotype is obtained when the minor allele at locus 2 or the major allele at locus 3, or both, is paired with the non-risk allele at rs16969968.
