Genetically informative studies of 'environment'.

In two papers derived from the same twin sample, Gillespie and his colleagues apply sophisticated methods of multivariate genetic modeling to address two separate issues relating to the development of cannabis use that have largely been overlooked by behavior geneticists: (a) the extent to which availability of cannabis may be influenced by heritable factors and the extent of overlap between genetic and environmental influences on availability and corresponding influences on initiation of use and the development of abuse (1); and b) the extent to which peer affiliations may be influenced by heritable factors and whether the overlap between peer affiliations and drug use may be explained by common or overlapping genetic and shared environmental influences (2). Their findings challenge several widely held preconceptions. Firstly, while both peer affiliations and drug availability have frequently been conceptualized as environmental risk factors, Gillespie et al demonstrate moderate heritable influences on both these measures. Additionally, by highlighting the multi-stage processes underlying the development of cannabis (and other drug) abuse, they invite us to think more critically about not just the extent but also the nature of the genetic and environmental influences that influence each of these progressions. While it might be hypothesized that environmental influences would be relatively more important in early stages of drug use and genetic factors being relatively more important in the later stages (e.g., genetic effects on withdrawal, a component of dependence), perhaps one of the more intriguing results reported by Gillespie et al (1) was the relatively high degree of overlap between the genetic influences on cannabis initiation and those on abuse. These findings may suggest that the current DSM conceptualization of abuse is tapping into liability to use the drug more than sensitivity to the effects of cannabis administration. This high degree of genetic commonality is particularly intriguing and raises important issues for the design of genomic studies of cannabis use disorders (3). The second paper suggesting that cannabis use may influence peer affiliations offers insight into one intriguing possible mechanism underlying the apparent and highly controversial gateway effects of cannabis. While cannabis use typically precedes the use of other illicit drugs, only a minority of individuals who use cannabis progress to the use of other drugs and it remains plausible that associations between early onset cannabis use and progression to the use of other illicit drugs simply reflect common predisposing factors associated with both early onset cannabis use and with the use of other drugs (4). However, studies which have attempted to control for such influences, including both peer affiliations preceding the onset of cannabis use and heritable predispositions, have been unable to fully discount the possibility that these associations may be causal. Nonethless, potential mechanisms underlying any such causal associations remain elusive (5-7). Pharmacological effects of early cannabis exposure seem an unlikely explanation (7): typical patterns of early onset cannabis use involve relatively low/infrequent use. Fergusson et al (7) have proposed that early onset cannabis use may set in train a process of affiliating with delinquent/ drug using peers and disengagement from traditional pursuits that in turn provide access to and encourage the use of other drugs. There is some support for this hypothesis: Fergusson et al (7) have shown that early onset cannabis use is associated with increased probability of affiliating with delinquent or substance using peers while one of the most robust sequelae appears to be disengagement from education (8, 9). Gillespie et al’s results also appear consistent with this hypothesis as they concluded that the genetic and environmental processes associated with early onset cannabis use also influence deviant peer group affiliations. An alternative explanation of the links between early onset cannabis use and subsequent use of other illicit drugs is that access to cannabis provides increased access to other drugs (10). Nonetheless, previous studies based in the Netherlands, where cannabis use has been depenalised, have failed to disprove the hypothesis that early cannabis use may be associated with subsequent hard drug use(6, 12), suggesting that links between cannabis and other illicit drug use can not be fully explained by links between the cannabis and other illicit drug markets. However, as noted by Gillespie, despite the more permissive legal framework in the Netherlands, rates of cannabis use remain markedly lower there than in the US and thus, it remains plausible that cannabis use may represent as much a norm violating behavior there as it does in countries in which cannabis remains illegal. While Dutch cannabis policy may be achieving its core goals, the persisting associations between early cannabis use and experimentation with other illicit drugs begs us to consider whether, in addition to legislation, social intolerance (which may be reflected by measures of peer deviance and availability) may contribute, via genetic and environmental pathways, to the relationship between cannabis and other illicit drug use. Overall, these papers highlight the value of behavior genetic research for understanding not only genetic influences but, more broadly, for understanding causal mechanisms underlying environmental exposures and such designs have great value in elucidating the course of exposure to environmental influences. The work by Gillespie and colleagues also sets the stage for future measured/unmeasured gene x environment analyses - such efforts, that attempt to characterize moderation of genetic vulnerability to cannabis use disorders by availability and peer deviance, will have to systematically control for the important effects of gene-environment correlation (13) - the likelihood that genetic variation, actively, evocatively and passively, mediates the likelihood of selecting or receiving novel environmental milieu.