Interest in PER2 as a candidate gene for alcohol use resulted from animal studies [11]. Earlier experiments in rodents have shown that genetic variation in PER2 is associated with a hyperglutamatergic state, which in turn leads to a higher level of alcohol use. The pharmaceutical drug acamprosate is supposed to act on this mechanism in order to reduce stress-induced craving. The present investigation provides no evidence for the exact mechanism by which the specific PER2 genotype studied protects against risk of alcohol problems. In particular, our findings leave open the question as to how exposure to stress influences pathophysiological pathways by which the gene-environment interaction observed in our study is mediated. SNP rs56013859 is localized in the third intron of the Per2 gene and is not in linkage disequilibrium (LD) with common variants analyzed in Hapmap. Hypotheses on the functional role of variation in PER2 suggest that SNP rs56013859 may alter the binding motives for transcription factors Sp1, c-myb, and nuclear factor B, suggesting a possible regulatory function of this SNP in transcriptional activation of PER2 [11]. However, one limitation
