Our analysis demonstrating that strong associations between CHRNA5-A3-B4 variants and nicotine dependence are seen only amongst smokers who began daily smoking relatively early in life, coupled with the detailed molecular definition of the CHRNA5-A3-B4 haplotype structures generated from resequencing, supports the hypothesis that the disease outcome effects of rs1051730, and other surrogate markers for Haplotype A, are mediated by nicotine addiction. This evidence concerns the gene CHRNA5 and nicotine dependence.