Within the subjects with SNP8^T/T, we observed that SNP3^G+ nominally significantly increased the risk for CD (P=0.026). Although this relationship fails rigorous criteria for statistical significance after correcting for multiple tests, the association may not be a random false positive. Within the SNP3-containing haplotype block (Figure 1), a SNP, rs806380, which is correlated with SNP3 (r2=0.63), was reported to be associated with cannabis dependence symptoms in an adolescent Caucasian sample (Hopfer et al 2006); a TAG haplotype in the SNP3-containing haplotype block was reported to be associated with polysubstance abuse in an EA sample (Zhang et al 2004). Further, another SNP in this SNP3-containing haplotype block, i.e., rs2023239, was reported to be associated with CB1 binding in the prefrontal cortex (Hutchison et al 2008), supporting that this SNP3 locus may play a role in substance dependence. SNP3 per se could alter RNA secondary structure (IDT SciTools: http://www.idtdna.com/SciTools/SciTools.aspx). RAVEN [regulatory analysis of variation in enhancers; (Andersen et al 2008)] predicts that SNP3 is located within a conserved region (phastCon score>0.4) and may be a binding site for transcription factors and thereby influence the efficiency of CNR1 transcription.
