Since the 1980s, a broad scientific consensus has been established that nicotine dependence (ND) is the primary factor maintaining smoking behaviour.3 We and others have shown strong evidence for the involvement of genetics in ND, with an average heritability of 0.56.4, 5 In the past dozen years, considerable efforts have been exerted to identify the genetic factors underlying ND. However, only three widely accepted “successes;” i.e., the neuronal nicotinic acetylcholine receptor gene clusters on chromosomes 15 (CHRNA5/A3/B4)6-20 and 8 (CHRNB3/A6)13, 15, 18, 21-25 and the genes encoding nicotine-metabolizing enzymes on chromosome 19 (CYP2A6/A7),16, 18, 26-28 meet community standards for significance and replication.29 These few triumphs stand in contrast to the limited heritability they explain; e.g., the most significant synonymous single-nucleotide polymorphism (SNP) rs1051730 (p = 2.75 × 10−73) in CHRNA3 accounted for only 0.5% of the variance in cigarettes smoked per day (CPD) in a meta-analysis of 73,853 subjects.16 Researchers have suggested that “missing heritability” is merely hidden and that additional loci can be discovered in GWAS with larger samples,30, 31 not to mention that the largest ND GWAS to
