Our analyses provide corroborative support for nicotinic acetylcholine receptor genes as risk genes for smoking-related traits: CHRNA5 (rs576982, p=3.40E-19, chr. 15; this region includes rs16969968, a well-established functional missense polymorphism [D398N] in CHRNA5, p=2.47E-12), CHRNB2 (rs45490696, p=1.45E-09, chr. 1), CHRNA2 (rs2741339, p=5.21E-17, chr. 8), and CHRNA4 (rs2273500, p=2.84E-22, chr. 20). Second, we identified associations with variants in several genes that modulate dopaminergic transmission, such as the dopamine receptor D2 (DRD2: rs34632468, p=1.04E-11, and rs4936277, p=1.81E-09, chr.11), known for its relationship with dopamine and reward,34 previously associated with nicotine dependence35 and implicated in a recent large-scale GWAS of addiction;36 dopamine beta-hydroxylase (DBH: rs2007153, p=9.35E-21, and rs2519155, p=7.25E-13, chr.9), which encodes an enzyme necessary to convert dopamine to norepinephrine and has been consistently implicated in smoking behaviors;13,37 lysine demethylase 4A (KDM4A: rs489319, p=1.61E-11, chr. 1), previously found to interact with dopaminergic agents and implicated in problematic opioid use;38 phosphodiesterase 4B (PDE4B: rs7528604, p=5.68E-10, chr. 1), which has regulatory effects on dopaminergic pathways and has been implicated in GWAS of externalizing behaviors,39 smoking initiation,37,39 and general liability for addiction;36 and neural cell adhesion
