Despite extensive smoking-control efforts, > 20% (or > 45 million) of American adults continue to smoke (3). There is a substantial genetic component underlying smoking behavior, with a heritability > 50% as demonstrated in studies with twins (4). The specific genes underlying smoking behavior, however, remain largely unknown. To date, more than 20 whole genome linkage studies have identified a number of loci potentially linked to smoking behavior, but few of these loci have been replicated across studies with high statistical significance (for review, see (5)). Genetic association studies have also implicated several genes associated with smoking behavior, such as GABAB2 (6), DOPA decarboxylase (7), and nicotinic acetylcholine receptor α4 subunit (CHRNA4) (8) and α5/α3/β4 cluster on chromosome 15 (9). However each of these studies focused on genes with known significance in neural biology and, consequently, these association studies were not designed to identify potentially novel genes/regulatory mechanisms underlying smoking behavior. Moreover, most of the genes implicated in these association studies await further confirmation from independent studies.
