gene cluster, were shown previously to have independent associations with smoking quantity8 (see also36). The SNPs rs8032771 and rs12595538, which are located downstream of the CHRNA5-CHRNA3-CHRNB4 gene cluster, were in weak linkage-disequilibrium (LD) with rs16969968 and rs6495308 (R2≤0.10), and were genome-wide significant in the largest meta-analysis7 (p<1×10-16 for both; p-values for these SNPs were not published in the other two meta-analyses). In 19q13.2, we selected the SNPs rs7937 and rs4105144. Following two previous studies using multi-locus measures of genetic risk for smoking, we assumed an additive model and summed alleles associated with higher smoking quantity to calculate the GRS.25,27 Because no reference data exist to determine the exact contributions of individual SNPs in our GRS to developmental phenotypes of smoking behavior, we used un-weighted counts of risk alleles to construct the score.
