SNPs and mRNA expression was most pronounced in the central amygdala. The rs2576573 A allele, observed to be more frequent in cannabis subjects, was associated with higher PENK mRNA expression in the central amygdala of the postmortem population in control subjects. This would seem contrary to predictions based on animal studies since upregulation of amygdala PENK mRNA expression predicts heightened anxiolytic responses and cannabis subjects exhibited more Neuroticism/anxiety. However, it is important to note that it was not possible to study mRNA expression in the brains of cannabis users, so whether the same relationship exists between the A rs2576573 allele and mRNA expression in cannabis-dependent subjects needs to be investigated. Nevertheless, the current observation does document for the first time that PENK mRNA expression, particularly in the amygdala, directly associates with these polymorphic noncoding PENK SNPs. The fact though that the entire PENK gene is in strong LD suggests that the causative mutation still remains to be identified.
