The interaction between cannabis use and a CB1 - related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing

Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene ( CNR1 ) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score ( CNR1 -PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1 , and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1 -PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1- PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1- PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1 -related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis.