Allele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus

Gemma Nicoll, Scott Davidson, Lynne Shanley, Ben Hing, Marissa Lear, Peter McGuffin, Ruth Ross, Alasdair MacKenzie

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Polymorphisms within intron 2 of the CNR1 gene, that encodes cannabinoid receptor 1 (CB1), have been associated with addiction, obesity and brain volume deficits. We used comparative genomics to identify a polymorphic (rs9444584-C/T) sequence (ECR1) in intron 2 of the CNR1 gene that had been conserved for 310 million years. The C-allele of ECR1 (ECR1(C)) acted as an enhancer in hypothalamic and dorsal root ganglia cells (DRG) and responded to MAPK activation through the MEKK pathway but not in hippocampal cells. However, ECR1(T) was significantly more active in hypothalamic and DRG cells but significantly, and in contrast to ECR1(C), was highly active in hippocampal cells where it also responded strongly to activation of MAPK. Intriguingly, rs9444584 is in strong linkage disequilibrium (LD) with two other SNPs (rs9450898 (r2=0.841) and rs2023239 (r2=0.920) that have been associated with addiction, obesity (rs2023239) and reduced fronto-temporal white matter volumes in schizophrenia patients as a result of cannabis misuse (rs9450898). Considering their high LD and the increased response of ECR1(T) to MAPK signalling compared to ECR1(C) it is possible that the functional effects of the different alleles of rs9444584 may play a role in the conditions associated with rs9450898 and rs2023239. Further analysis of the different alleles of ECR1 may lead to a greater understanding of the role of CNR1 gene mis-regulation in these conditions as well as chronic inflammatory pain.
Original languageEnglish
Pages (from-to)12828-12834
Number of pages7
JournalThe Journal of Biological Chemistry
Issue number16
Early online date23 Feb 2012
Publication statusPublished - 13 Apr 2012



  • addiction
  • cannabinoid receptors
  • cell signalling
  • gene regulation
  • genetic polymorphism
  • hypothalamus
  • neurons
  • obesity
  • transcription enhancers
  • hippocampus

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