In the present study, the interaction between two independent CNR1 variants, i.e., SNP3^G+ and SNP8^T/T, was associated with CD in an EA family sample. The association was replicable in an EA case-control sample. Sliding window haplotype analysis in the EA family sample showed that the haplotype constructed from SNP8 and its two neighboring SNPs displayed a higher association signal (P=0.007) than SNP8 alone, suggesting that SNP8 is in LD with a disease–influencing locus rather than being a risk locus itself. This SNP8-linked risk locus could be located either in the coding region of CNR1 directly affecting the function of the CB1 protein or in the 3’UTR regulating translational efficiency, mRNA stability, or polyadenylation signals. Prediction of miRNA target sites for CNR1 suggests that the 3’UTR region of CNR1 might be targeted by miRNAs affecting posttranscriptional CNR1 expression (http://www.targetscan.org). SNP8 was in complete LD with a well-studied polymorphism in CNR1, i.e., SNP7. This SNP is the Thr453Thr synonymous variant, located in the coding region of CNR1. Although it did not show association with CD, it showed nominal association with CIP. This SNP was reported to be associated with alcohol withdrawal delirium in an unrelated German population (Schmidt et al 2002).
