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Background
Cannabis is a psychoactive drug with a long history of illegal use, mainly for recreational purposes. Chronic consumption of cannabis is associated with various health complications, including cognitive deficits, psychiatric disorders, and cancers.
Recently, many countries throughout the world have approved the use of cannabis for medicinal purposes and decriminalized its recreational use. In the United States, medical use of cannabis has been authorized in 37 states, whereas the recreational use of cannabis has been approved in 19 states. In Europe, Malta has fully legalized recreational cannabis.
With the recent changes in cannabis law, a gradual increase in the prevalence of cannabis use disorder has been observed worldwide.
The study
A GWAS meta-analysis of cannabis use disorder was conducted using the Million Veteran Program database, which is one of the largest biobanks in the world that complies with genetic, health, and lifestyle data to facilitate genetic research.
Additionally, a meta-analysis was conducted on data obtained from 1,054,365 individuals of European, African, mixed American, and East Asian ancestries designated by the reference panel used for assignment.
Single nucleotide polymorphism (SNP)-based heritability was calculated within each ancestry using population-specific methods.
Important observations
A total of 22 independent genome-wide significant (GWS) loci were identified within European ancestry, two GWS loci within African ancestry, one GWS locus within admixed American ancestry, and two GWS loci within East Asian ancestry.
The lead SNP for European ancestry was near the cholinergic receptor nicotinic alpha 2 subunit-encoding gene. For African ancestry, the lead SNP was in an intron of a gene that encodes for a pH-dependent proton-coupled amino acid transporter for glycine, alanine, and proline.
For admixed American ancestry, the lead SNP was in an intergenic region downstream of leucine-rich repeat-containing 3B. For East Asian ancestry, the lead SNP was intronic to the semaphorin 6D-encoding gene.
Comparative analysis of cannabis use disorder and cannabis use traits with a range of psychiatric and nonpsychiatric traits showed a much more substantial overlap of cannabis use disorder with pathological and negative traits.
The calculation of SNP-based heritability within each ancestral group identified significant SNP-based heritability for three larger ancestries, including European, African, and mixed American ancestries.
The comparison of genetic correlations between cannabis use disorder and cannabis use revealed that the strongest positive correlations are related to smoking initiation and alcohol dependence. Comparatively, the strongest negative correlations are related to the age of first intercourse and smoking cessation.
Further analysis identified a bidirectional causal relationship between cannabis use disorder and schizophrenia. Regarding the differences between cannabis use and cannabis use disorder, the analysis showed that cannabis use disorder is much more closely associated with psychopathology.
A unidirectional causal effect of multi-site chronic pain on cannabis use disorder was observed in the study. This indicates that chronic pain might act as a driving factor for cannabis use disorder.
The analysis further identified a unidirectional causal effect of cannabis use disorder on lung cancer. Conditional analysis of this result with smoking initiation did not significantly alter the relationship between cannabis use disorder and lung cancer. However, the conditional analysis with cigarettes each day mitigated this relationship.
A transcriptome-wide association study identified 36 and 15 genes using adult and fetal brain frontal cortex expression, respectively. DALR Anticodon Binding Domain Containing 3 (DALRD3) was the only common gene in these gene sets. Nonsense mutations in this gene are known to be associated with developmental delay and early-onset epileptic encephalopathy.
The observed gene associations included four distinct GWAS loci, including DALRD3 (both fetal and adult), ERCC8 (fetal), RP11-629G13.1 (adult), and PHLPP2 (adult). Proteins encoded by these genes are associated with various cancer types, including breast cancer, esophageal cancer, and multiple myeloma.
The estimation of SNP-based heritability of cannabis use disorder showed significant enrichments for the fetal brain frontal cortex but not for the adult brain cortex. This enriched fetal SNP-based heritability indicates that in the developing brain, genetic factors might play a role in inducing cannabis use disorder, even in the absence of cannabis exposure.
Study significance
The study finds a significant difference between cannabis use and cannabis use disorder. Genetic liabilities to cannabis use disorder exhibit a much stronger association with psychopathology and disability. Notably, the study finds a causal link between cannabis use disorder and lung cancer risk.
