It is important to comment on the differences in allele frequencies that are present in Caucasians and African Americans, because ethnicity may be an important factor in the biological relevance of these SNPs. Even though all ethnic groups could be analyzed together when using the family-based PBAT analysis which controls for stratification, the association of rs2304297 became more significant when Caucasians were analyzed separately. This may be due to differences in the size of the LD blocks in Caucasians versus African Americans. There is only a small probability that rs2304297 is “the functional” allele, so the strength of association will depend on the level of LD between rs2304297 and the actual disease allele. Based on data from the HapMap project NCBI Build 35 (2003) as well as the results of genotyping presented here, the LD block which contains rs2304297 extends beyond exon 4 of CHRNA6 in Caucasians but is weaker in African Americans. In addition, as mentioned above, the differences between the results within ethnicities may be affected by genetic background, a well documented factor in genetically engineered mouse studies (Crabbe et al, 2006), but relatively unexamined in humans.
