Our top gene associated with lifetime cannabis use was NCAM1, a known candidate for nicotine dependence.45 The role of NCAM1 is to regulate pituitary growth hormone secretion as a membrane-bound glycoprotein that mediates cell–cell contact by hemophilic interactions.46 NCAM1 is part of the NCAM1–TTC12–ANKK1–DRD2 (NTAD) gene cluster, which is related to neurogenesis and dopaminergic neurotransmission. Importantly, the NTAD cluster has been associated with smoking behavior and nicotine dependence,45, 47, 48, 49, 50, 51, 52 alcohol dependence,53, 54 heroin dependence,55 as well as other substance use disorders.54 Although it is plausible that NCAM1 is capturing pleiotropic risks underpinning the liability to licit and illicit substance use in general, we note that NCAM1 was not identified either by the Tobacco Alcohol and Genetics consortium or other consortia for cigarette smoking.30, 31, 32 The functions of the putative variants responsible for the associations in the candidate-gene studies remain to be determined.
