rs1049353 is exonic but synonymous, indicating that its impact on the activity of CNR1 is not attributable to a coding change. However, synonymous SNPs can induce widespread modification in protein formation and there is preliminary evidence that rs1049353 is in the region of an exon splice enhancer (ESE), responsible for recruiting spliceosomes and other machinery necessary for accurate splicing of exons during translation67. Future studies should also explore whether the A/A (and A/G) genotypes of rs1049353 are associated with change in endocannabinoid activity. Finally, rs1049353 is in high linkage disequilibrium (r2=0.94) with rs4707436 which resides in the 3′ untranslated region of CNR1, which could have potential regulatory effects. Similar other untyped causal variants may also exist.
