In contrast to the studies of alcohol dependence, GWAS of smoking behavior have reported consistent and compelling genetic evidence for association. The first GWAS using a case-control sample reported evidence that variants within the nicotinic acetylcholine receptor (nAChR) subunit genes on the long arm of human chromosomes 15 (CHRNA5-CHRNA3-CHRNB4) and 8 (CHRNA6-CHRNB3) influence risk for nicotine dependence, as defined by scores on the Fagerström test for nicotine dependence (17). The chromosome 15 association has been replicated in subsequent GWAS either directly or indirectly using highly correlated SNPs (r2 > 0.8), with cigarettes per day (CPD) as a quantitative variable to define heavy- and light-smoking individuals (13, 17, 123, 140). Genome-wide association meta-analyses for CPD further confirmed that variants in CHRNA5, CHRNA3, and CHRNB4 are associated with the risk of developing heavy smoking (87, 124, 124a). In addition, the GWAS reported by Thorgeirsson et al. (124) showed that variation in the CHRNA6-CHRNB3 gene cluster on human chromosome 8 is associated with CPD at a genome-wide significance level.
