We derived the genetic risk score (GRS) from 3 recent meta-analyses of GWAS that used as their phenotype cigarettes smoked per day.7-9 To construct the genetic risk score (GRS), we considered single-nucleotide polymorphisms (SNPs) from regions with genome-wide significant associations in at least two meta-analyses: All 3 meta-analyses identified SNPs in the q25.1 region of chromosome 15 containing the CHRNA5-CHRNA3-CHRNB4 gene cluster. Two meta-analyses identified SNPs in the q13.2 region of chromosome 19 containing the gene CYP2A6. These genes influence nicotine response and nicotine metabolism, have been linked with nicotine dependence, and are candidate genes in research into the development of smoking behavior.26,29-35 Therefore, we focused our inquiry on the top GWAS SNPs in these two regions (Supplemental Methods). In 15q25.1, we selected the SNPs rs16969968, rs6495308, rs8032771, and rs12595538. The SNPs rs16969968 and rs6495308, which fall within the CHRNA5-CHRNA3-CHRNB4 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
