The unequivocal evidence of http://www.selleckchem.com/products/z-vad-fmk.html association of CHRNA5-A3-B4 variants with heaviness of smoking and other tobacco use phenotypes also addresses one concern raised regarding G �� E effects, namely the presence of interaction effects in the absence of main effects (Flint & Munaf��, 2008). What remains is to consider what environmental factors may plausibly influence the probability of exposure to tobacco (i.e., experimentation) and thereby moderate the expression of genetic liability for subsequent dependence. One such factor is parental monitoring (i.e., the extent to which parents are aware of their child��s activities, peer group, etc.), which is independently known to be associated with the likelihood of smoking experimentation and initiation (Forrester, Biglan, Severson, & Smolkowski, 2007).

Recent work indicates that parental monitoring may indeed moderate the association of CHRNA5-A3-B4 variants with the subsequent development of tobacco dependence and heavy smoking (Chen, Johnson, et al., 2009), although this study relied on retrospective self-report of parental monitoring and requires replication in a prospectively assessed sample. Similar moderating effects of parental monitoring have been reported in relation to genetic associations with externalizing behaviors (Dick et al., 2009, 2011) and alcohol use (Kendler, Gardner, & Dick, 2011). This is consistent with evidence from twin studies, which suggests that at high levels of parental monitoring, environmental influences are the dominant influence on adolescent smoking, but at low levels genetic influences are more important (Dick et al.

, 2007). While parental monitoring therefore appears to be a promising environmental factor, which may moderate the expression of genetic effects, the challenge will be to identify other factors, which may operate in similar ways. Environmental factors influencing the likelihood of initiation, such as peer smoking (Scherrer et al., 2011), are likely targets. It is also possible that there may be particular developmental Anacetrapib risk windows when smoking initiation is more likely to result in the expression of genetic influences on dependence liability, based on known relationships between early smoking initiation and subsequent dependence (Khuder, Dayal, & Mutgi, 1999). In addition, it will be important to identify further variants beyond the CHRNA5-A3-B4 cluster which robustly associate with tobacco use phenotypes, a project which is rapidly making progress (Furberg et al., 2010; Liu et al., 2010; Thorgeirsson et al., 2010).