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 and major-minor diplotype. It is also possible that multiple rare variants underlie these findings, as has been suggested in general for disease associations with common SNPs [33]. It remains possible that these associations with locus 1, locus 2 and locus 3 are reflecting correlation with yet another underlying, untyped variant that alone explains the altered biology leading to risk. However, biological involvement of multiple loci appears more likely given that two of these loci represent two distinct, relevant functional consequences: namely, locus 1 (the amino acid change at rs16969968) is associated with altered receptor response to a nicotine agonist in vitro [19], and locus 3 (rs588765 and correlates) is associated with altered mRNA levels of CHRNA5 in brain and lung tissue [22], [24]. Further investigation via resequencing, biological/functional assays, and animal models is needed to dissect the causal biology that underlies the statistical evidence.
