In a recent study published in Nature Genetics, researchers conducted a genome-wide association study (GWAS) to achieve novel insights into the pathophysiology of cannabis use disorder and public health concerns related to the disorder.

Study: Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications. Image Credit: ShutterstockProfessional / Shutterstock.com

Background

Cannabis is a psychoactive drug with an extended history of illegal use, mainly for recreational purposes. Chronic consumption of cannabis is related to various health complications, including cognitive deficits, psychiatric disorders, and cancers.

Recently, many countries throughout the world have approved using cannabis for medicinal purposes and decriminalized its recreational use. In the US, 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 within 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 considered one of the most important biobanks on the planet that complies with genetic, health, and lifestyle data to facilitate genetic research.

Moreover, 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 task.  

Single nucleotide polymorphism (SNP)-based heritability was calculated inside each ancestry using population-specific methods. 

Essential observations

A complete of twenty-two independent genome-wide significant (GWS) loci were identified inside European ancestry, two GWS loci inside African ancestry, one GWS locus inside admixed American ancestry, and two GWS loci inside 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 evaluation of cannabis use disorder and cannabis use traits with a variety of psychiatric and nonpsychiatric traits showed a rather more substantial overlap of cannabis use disorder with pathological and negative traits.

The calculation of SNP-based heritability inside each ancestral group identified significant SNP-based heritability for 3 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 evaluation identified a bidirectional causal relationship between cannabis use disorder and schizophrenia. Regarding the differences between cannabis use and cannabis use disorder, the evaluation showed that cannabis use disorder is rather more closely related to psychopathology.

A unidirectional causal effect of multi-site chronic pain on cannabis use disorder was observed within the study. This means that chronic pain might act as a driving factor for cannabis use disorder.

The evaluation further identified a unidirectional causal effect of cannabis use disorder on lung cancer. Conditional evaluation of this result with smoking initiation didn’t significantly alter the connection between cannabis use disorder and lung cancer. Nonetheless, the conditional evaluation with cigarettes every 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 one common gene in these gene sets. Nonsense mutations on this gene are known to be related to developmental delay and early-onset epileptic encephalopathy.

The observed gene associations included 4 distinct GWAS loci, including DALRD3 (each fetal and adult), ERCC8 (fetal), RP11-629G13.1 (adult), and PHLPP2 (adult). Proteins encoded by these genes are related to 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 within the developing brain, genetic aspects might play a job in inducing cannabis use disorder, even within the absence of cannabis exposure.    

Study significance

The study finds a big 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.