Haplotypes located in the CHRNA5-A3-B4 subunit JQ1 molecular weight cluster were characterized and correlated to the Fagerstr?m Test for Nicotine Dependence (FTND; Heatherton, Kozlowski, Frecker, & Fagerstr?m, 1991). Specifically, the major haplotypes A and C (HA, HC) were associated with high and low FTND scores, respectively (Weiss et al., 2008). Haplotype A includes the risk alleles T of rs1051730 and A of rs16969968 that have been associated with nicotine dependence in prior studies (Saccone et al., 2007; Thorgeirsson et al., 2008). Several features of the Weiss et al. (2008) work are noteworthy. First, this research demonstrates the presence of a significant gene �� environment interaction. Specifically, strong associations (p=2.0��10?5) between CHRNA5-A3-B4 variants and nicotine dependence were seen only among smokers who began daily smoking relatively early in life (e.

g., at age 16 or younger; early-onset smokers). No associations (p=.38) with haplotypes in the CHRNA5-A3-B4 cluster were seen in smokers initiating daily smoking at age 17 or later. Second, the obtained associations were of substantial magnitude (odds ratio [OR]=1.82, 95% CI=1.39�C2.39). Third, the research is notable because the same pattern of associations was observed in three large (n = 2,210) independent samples. Credence in the Weiss et al. (2008) results is bolstered by other research that found signals for nicotine dependence in the same region. In a small study of Israeli women, Greenbaum et al. (2006) obtained a suggestive association between their measure of dependence and a CHRNA3 SNP, rs1051730 (see also Thorgeirsson et al.

, 2008). Sherva et al. (2008) have reported a significant association between rs16969968 and smoking status as well as experiencing a ��pleasurable buzz�� in response to early experimentation with smoking. Studies examining the CHRNA5-A3-B4 cluster as candidate genes (e.g., Berrettini et al., 2008; Saccone et al., 2007) found evidence for associations between common variants in the cluster and their respective phenotypes. Three new genome-wide association studies provide strong evidence for an association between CHRNA5-A3-B4 variants and lung cancer, but they differ on whether the connection is direct or mediated by smoking behavior (Amos et al., 2008; Hung et al., 2008; Thorgeirsson et al., 2008). Previous CHRNA5-A3-B4 research has been based on a limited assessment of nicotine dependence.

Several of the earlier studies related the CHRNA5-A3-B4 variants to the FTND, either to the total score or to individual items (e.g., Greenbaum et al., 2006; Saccone et al., 2007; Cilengitide Thorgeirsson et al., 2008; Weiss et al., 2008). Factor analyses typically show that the FTND items reflect only a smoking heaviness or compulsive smoking factor and a secondary morning smoking factor (Baker et al., in press; Breteler, Hilberink, Zeeman, & Lammers, 2004; Nonnemaker & Homsi, 2007; Radzius et al.