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Identification of genetic biomarker signatures associated with cannabis pharmacokinetics and tolerability

ABSTRACT: Medical cannabis has been increasingly prescribed for a range of conditions including epilepsy, chronic neuropathic pain, and chemotherapy-induced nausea and vomiting. The benefits and possible adverse events of medical-grade cannabis products vary between patients, suggesting that genetics may play a role in the pharmacokinetics of the cannabinoids, yet regulatory restrictions have led to limited clinical studies. This study is aimed at identifying a genetic signature that is predictive of the pharmacokinetics of tetrahydrocannabinol (THC), the principal intoxicating chemical compound derived from cannabis. We have identified 55 variants among 38 genes that were overrepresented in either the Low-THC or High-THC groups.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148835 | GEO | 2020/04/18

REPOSITORIES: GEO

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Project description:Background: Adolescent cannabis use leads to long-lasting behavioral changes involving cognitive and reward processes. However, the underlying molecular mechanisms are not well understood. To address this limitation, we performed gene network analyses using transcriptomic data from mice exposed during adolescence to Δ-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: We injected vehicle or THC in female and male mice during the entire adolescence period. Two weeks following the last exposure, we measured recognition memory, social interaction and anxiety-related behaviors. We generated 120 RNA-seq datasets from 5 brain regions for each mouse. We performed differential gene expression analysis and constructed co-expression networks to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, biological pathways, and cellular specificity. Further, we integrated THC-correlated gene networks with human traits from genome-wide association studies and performed key driver analysis to identify potential regulators of disorder-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females, which coincided with larger transcriptional alterations in the female brain. Gene network analyses identified brain region-, cell type- and sex- specific co-expressed genes (“modules”) dysregulated by THC. THC-induced memory deficits in females were correlated with disruption of gene networks involved in endocannabinoid signaling and inflammation. Additional THC-correlated modules in both sexes involved converging pathways related to dopamine signaling and addiction processes. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Further, modules altered by THC treatment were enriched in genes relevant for human cognition and schizophrenia. Conclusions: These findings provide novel insights concerning the genes, cell types, and pathways underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner, and highlight the connection between adolescent cannabis use and neuropsychiatric disorders in humans.

Dataset Information

Identification of genetic biomarker signatures associated with cannabis pharmacokinetics and tolerability

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