This chromosome 15q24-25.1 region also harbors SNPs that are correlated with each other and associated with brain mRNA levels of CHRNA5 in European-descent samples ([33, 34]). Our second major finding is that in African-Americans, these expression-associated SNPs are associated with nicotine dependence. The evidence is nominally significant (p = 0.045, OR = 0.79 (0.63–0.99) for rs555018) in our modestly powered African-American sample. It is intriguing that in European-Americans, single-SNP association at rs555018 is not seen; however, when rs16969968 is included as a covariate, rs555018 does significantly alter risk. Joint genotype analysis clarifies that in the presence of “GG” at rs16969968, the major allele “T” at rs555018 appears to confer protection in European-Americans; however in African-Americans the minor allele “C” at rs555018 is the one more frequent in controls. These contrasting effects are difficult to interpret, but suggest that mRNA levels of CHRNA5, and thus nicotine dependence risk, may be influenced by additional variants in the region.
