Functional polymorphisms within regulatory, intronic or untranslated regions that affect α5 receptor expression levels may modulate nicotine dependence (Wang et al., 2009, 2009b; Buckland et al., 2005). Indeed, rs2036527:G>A, located at -6246 from the transcription start site of CHRNA5, obtained genome-wide statistical significance in a meta-analysis of African-American GWAS (David et al., 2012) and a meta-analysis of European GWAS identified the CHRNA5 5′UTR SNP rs55853698:T>G as having the highest statistical significance for the CPD phenotype (Liu et al., 2010). The minor allele (‘G’) of rs55853698:T>G is in moderate LD (D′=0.872, r2=0.52) with the rs2036527:G>A minor allele (‘A’) in our African-American heavy smoker population (Figure 2). Thus, rs2036527:G>A may be a proxy for greater expression of CHRNA5 in African-Americans (David et al., 2012) and other ethnic populations where LD between rs2036527:G>A and rs55853698:T>G is perfect (1kGenome_CEU: D′=1.0, r2=1.0).
