Smoking is a risk factor for many serious diseases and a leading cause of preventable deaths worldwide.1 Genome-wide association studies relying on common markers have yielded loci associating with smoking behavior, including genomic regions containing genes encoding various subunits of nicotinic acetylcholine receptors (nAChRs) on chromosomes 15q25 (CHRNA5/CHRNA3/CHRNB4),2, 3 8p11 (CHRNB3/CHRNA6)3 and recently 20q11 (CHRNA4).4 Sequence variants within the CHRNA5/CHRNA3/CHRNB4 cluster on chromosome 15q25 have been shown to associate with the number of cigarettes smoked per day (CPD),2, 5 nicotine dependence (ND)2, 6 and the smoking-related diseases lung cancer (LC),2, 7, 8, 9 peripheral arterial disease (PAD),2 chronic obstructive pulmonary disease (COPD)10 and upper aerodigestive tract cancer.11 The role of the CHRNA5/CHRNA3/CHRNB4 locus for smoking, ND and the consequences of smoking was established through human genetics approaches, and these initial findings have paved the way for basic research aimed at elucidating the underlying mechanisms.12
