Our next key observation is that less common SNPs appear to be associated with nicotine dependence, suggesting that rarer variants in this gene cluster may have strong effects on susceptibility. In European-Americans, rs12914008 (MAF = 5%) is associated with nicotine dependence (p = 0.035, OR = 0.73 (0.54–0.97)). In the African-American sample, this SNP is very rare (0.6%) and affords little power to detect association, though in the combined analysis the evidence improves (p = 0.022, OR = 0.71 (0.53–0.95)). This SNP causes a missense change in CHRNB4 (threonine to isoleucine, T91I) and is also in LD (r2 = 0.8 in CEU) with rs8192475, a non-synonymous SNP in CHRNA3 (arginine to histidine, R37H). We also identified a novel SNP that is nominally associated with nicotine dependence in the full sample and has a frequency of 6% in European-Americans and 1% in African-Americans. These rarer variants are intriguing. Though we cannot conclude that these SNPs represent additional independent risk factors, they hint that this region may play a more complex biological role in risk for nicotine dependence than will be explained by common variants.
