Common SNPs were able to account for a fraction (12%) of the overall heritability of TUD (40–60%) as determined by prior family and twin studies.9,11 The multi-ancestral meta-analysis identified 88 independent loci, 18 times the number previously reported for nicotine dependence.27 These include corroborative support for the involvement of nicotinic acetylcholine receptor genes (CHRNA5-A3-B4, CHRNB2, CHRNA2, CHRNA4), which have been consistently associated with smoking behaviors,20 particularly in studies of self-reported CPD.13 Other variants identified are in genes that modulate dopaminergic and glutamatergic neurotransmission, compromising reward-based learning and facilitating drug-seeking behavior, and in BDNF, which is involved in memory consolidation processes,51 and a well-studied candidate gene in addiction.52 These and other candidates supported by TUD (e.g., PDE4B) were genetically correlated with other addiction phenotypes,36 emphasizing the shared neurobiological mechanisms of addiction.
