Regarding SNP coverage, our top nicotine dependence-associated CHRNA4 variants are 1000 Genomes–imputed SNPs not present on genotyping arrays or imputable from HapMap phase II in prior GWAS. Our most significantly associated SNP available in HapMap phase II (rs4809539, r2=0.19 and D′=0.67 with rs2273500 in EUR) had meta-analysis P=3.5 × 10−4. We evaluated the CHRNA4 region further using meta-analysis results from the largest prior GWAS of CPD by the Tobacco and Genetics Consortium.7 These results are presented in Supplementary Table 9. Among 57 HapMap phase II SNPs in the region (r2 ranging from 0 to 0.61 with rs2273500 in EUR), we found that rs4809539 was also the SNP that was most significantly associated with CPD (meta-analysis P=4.8 × 10−3); its T allele (frequency=0.06) was associated with higher CPD, consistent with an increased risk of nicotine dependence in our data. These results suggest that use of the FTND phenotype together with 1000 Genomes imputation enabled us to detect CHRNA4 variant associations with nicotine dependence that were genome-wide significant.
