Taken together, our meta-analysis results argue strongly for the existence of at least two statistically distinct loci in this region that affect risk for heavy smoking. In particular, both locus 1 and locus 3, which have known functional effects, are genome-wide significant in joint, mutually-adjusted analysis. The minor allele at locus 3 shifts from a marginally significant protective factor when considered alone to a robust risk factor when considered in combination with locus 1. The statistical evidence and negatively correlated alleles at locus 1 and locus 3 are consistent with at least two mechanistic models: distinct effects of two loci where the minor allele at each locus increases risk across a constant background at the other locus, or a haplotype dose effect where alleles at the two loci act in concert on the same haplotype strand. In the latter model, the minor-major and major-minor haplotypes each increase risk relative to the major-major haplotype, as can be seen in Table 6 once it is recognized that the rarity of the minor-minor haplotype implies that the double-heterozygote cell essentially represents the minor-major
