DBH is a strong functional candidate for influencing nicotine dependence. The dopaminergic system lies at the core of the brain’s reward pathway, and the DBH enzyme converts dopamine into norepinephrine. An upstream DBH SNP (rs3025343) was identified in a GWAS of smoking cessation (current vs former smokers)16–18 and later independently replicated.69, 70 Consistent with rs3025343-A being associated with reduced success of quitting smoking, its phenotypic profile has been expanded to include associations with: (1) heavier smoking (N=48,931 in the UK Biobank, P=1.2×10−5);24 (2) higher FTND scores (N=1,430 EUR participants, P=0.023);71 and (3) higher nicotine dependence risk in our EUR studies (N=28,677, meta-analysis P=1.7×10−5). Smaller p-values were found for other 1000G-imputed upstream DBH SNPs in the UK Biobank and our study (rs111280114 and rs56116178, respectively; Table 1); the minor alleles of these SNPs were similarly associated with increased risks among EUR studies (Supplementary Figure 7 for rs56116178). Because these DBH SNPs all occur at <1% frequency among AAs, studying DBH variation on nicotine dependence risk in this ancestry group will require larger sample sizes or an alternative study design.
