Significant genetic variations linked to cannabis use disorder identified in major global ancestries

In a recent study published in Nature Genetics, researchers analyzed genome-wide genotype data from the Million Veteran Program (MVP) expanding samples from Mass General Brigham BioBank (MGB) and iPSYCH2 using the Psychiatric Genomics Consortium (PGC)/iPSYCH1/deCODE study.

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

Background

Cannabis usage has been allowed in the United States (US) and other nations without a thorough assessment of its health implications.

Concerns regarding rising cannabis use disorder (CanUD), which is associated with several medical comorbidities, are developing as recreational use is decriminalized and medicinal usage is generally sanctioned.

More than a third of cannabis users develop CanUD, and information on the influence of legalization on increasing usage and disorders is conflicting. Chronic cannabis usage has been linked to cancer, cognitive deterioration, and an increased risk of schizophrenia.

CanUD may also lead to lower productivity and accidents as a result of drunkenness. Understanding CanUD risk factors is crucial, given the rising permissiveness surrounding its use.

About the study

In the present study, researchers conducted a genome-wide association study (GWAS) of cannabis use disorders involving >1.0 million individuals from three global cohorts and four ancestral populations.

CanUD was the focus of a genome-wide association research and meta-analysis in 1,054,365 individuals with four different ancestries as part of the Million Veteran Program (MVP). Single nucleotide polymorphism (SNP)-based heritability in the ancestries was calculated using population-specific methodologies and the cohort-derived linkage disequilibrium score regression (LDSC) covariate.

Transcriptome-wide association study (TWAS) data were analyzed using LSDC to detect eQTLs with significant expression in fetal and adult brain tissue.

The study was expanded to include individuals of African ancestry (AFR), and GWAS analyses were performed on people of Admixed American (AMR) and East Asian (EAS) ancestry. Mendelian randomization (MR) studies were also performed to investigate the causal links between lung cancer, chronic pain, substance use disorder (SUD), and physical activity.

Furthermore, genomic structural equation modeling (gSEM) was used to uncover the genetic connections between cannabis usage features and other mental and SUD variables. POPCORN was used to analyze genetic correlations versus available variables for CanUD in African ancestry.

A multi-trait conditional and joint analysis (mtCOJO) of cannabis use disorders trained on two characteristics of smoking using the genome-wide association study and Sequencing Consortium of Alcohol and Nicotine Use study (GSCAN) data was performed for the European ancestry (EUR).

Results

The researchers investigated the genetic link between chronic pain and CanUD, a conditional risk factor for lung cancer. The MR analysis showed that CanUD had a unidirectional causal impact on chronic pain, whereas a bidirectional causal effect on the initiation of smoking.

The conditioning analysis showed that following conditioning on smoking initiation, 18 of the 22 initial lead SNPs remained in the sample. CanUD conditioning on cigarettes daily produced identical results, with the 20-lead genetic loci that remained in the genome-wide significant (GWS) following conditioning.

Compared to the EUR meta-analysis, the multi-trait GWAS study found 34 lead single-nucleotide polymorphisms at 26 genetic risk loci, including four unique loci. CanUD had a genome-wide association study-equivalent sample population of 200,762 individuals, which increased the sample population of the meta-analytic research by 20%.

The multi-trait analysis of GWAS (MTAG) and GWAS studies showed ten genetic risk loci as statistically significant, whereas the remnant 16 variations were independent of the linkage disequilibrium (LD).

The team found two important factors: ‘unable to work,’ Townsend deprivation index, chronic pain, and the Fagerström Test for Nicotine Dependence (FTND). Factor 2 includes the number of sex partners, cannabis usage, and beginning to smoke regularly.

Factors 3 and 4 were Significantly connected with psychiatric features such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD) checklist score, generalized anxiety disorder symptoms, suicide attempts, and schizophrenia (SCZ).

CanUD, opioid use disorder, and AUD all had substantial relationships with factors 4 and 5. The study found 22 significant loci for CanUD in EUR, most of which were novel.

Conclusions

To summarize, cannabis use and cannabis-use disorders (CanUD) are genetically linked, with psychopathology and disability being more closely related. The heredity enrichment of SNPs in fetal brain tissue indicates the biological foundation for CanUD.

Bi-directional causal impacts between CanUD and SCZ and unidirectional impacts of multiple-site chronic pain on cannabis use disorders and lung cancer were observed.

CanUD shares a latent component with other drug-dependent features, indicating a link between cannabis use disorders and pulmonary cancer risk. Future research should explore addiction, tetrahydrocannabinol blood levels, and pain disorders.

Further research on individuals of different ancestries must replicate the findings and extend their applicability to all individuals.

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