A major question is whether the multiple SNP associations between CHRNA5-CHRNA3-CHRNB4 and nicotine dependence represent the effect of a single causal locus, or whether multiple, statistically distinct loci are involved. Our data lead us to believe that there are at least two distinct, biologically causal loci in this region. In our analyses, the association at rs578776 in European-Americans is not explained by the association at rs16969968. Similarly, the association at rs555018 in African-Americans is not completely explained by rs16969968. The high |D′| between the seloci, however, does not allow us to determine the effect of each locus in the presence of all possible genotypes at other loci.
