system (38). It is possible that variants of these PH-domain-containing proteins have an impact on the cell-signaling pathways that regulate neuronal plasticity, and thus could influence predisposition to ND. The µ-opioid receptor gene OPRM1 has been found to be associated with FTQ nicotine dependence (37) and plays a role in substance use and dependence across several drug classes (39–41). Two other previously identified candidate genes, DRD4 (42, 43) and COMT (44), are located at bin 11.1 and bin 22.1 respectively, each of which showed nominal significance in the primary GSMA of smoking behavior or MaxCigs24. Some other well known candidate genes, such as the NCAM1-TTC12-ANKK1-DRD2 gene cluster (45, 46) and DDC (47, 48), are not represented in any of the chromosomal regions identified. These findings might reflect the possibility that the effect size of these genes is too small to be detected by the current GSMA.
