Among the most replicated associations in addiction are those between polymorphisms in the nicotinic acetylcholine receptor gene cluster encoding the α5, α3, and β4 subunits (CHRNA5-A3-B4) with nicotine dependence [45-47], smoking behaviors [48, 49], and treatment response [50]. A majority of studies implicate a non-synonymous SNP, rs16969968, in CHRNA5 encoding an aspartic acid to asparagine substitution at codon 398 (a highly conserved residue), and a highly correlated proxy SNP, rs1051730, in CHRNA3. This variant (rs16969968) was initially identified in a candidate gene association study of nicotine dependent cases [45]. A proliferation of studies followed when multiple genomewide association studies unequivocally identified this variant as a contributor to genetic vulnerability for cigarettes smoked per day (CPD). Aggregating effect sizes across 73,853 subjects, investigators convincingly documented an association on the order of 10-73 for an association between rs1051730 and CPD [51, 52, 53••].
