First, we constructed a polygenic risk score in which we combined the top genetic variants (all SNPs reaching a P-value threshold of 5 × 10−7) described in the STOMP meta-analysis.18 We limited the polygenic risk score to include only variants associated with the number of cigarettes smoked per day (and not age of initiation, which was also analyzed in the STOMP meta-analysis) to limit phenotypic heterogeneity. This included six SNPs from multiple genes across chromosomes 15 and 1 (detailed in Table 2). SNPs were in modest linkage disequilibrium (r2 values ranged from 0.07 to 0.47), limiting the concern of redundancy in the genetic risk score (GRS). In cases where the original SNP was not available in the DNHS, a highly correlated (r2>0.9) proxy SNP was used in its place. Each of the SNPs was weighted by the marker information (risk allele and effect size) provided from the meta-analysis; each variant (risk allele) was summed to create an aggregate GRS, and those variants with a larger effect size (indicated by the β-coefficient) were given a greater weight. Scores were computed using PLINK.45
