CHRNA2 Under-Expression Is Linked to Cannabis Use Disorder

Post by Shireen Parimoo

What's the science?

With increasing legalization of cannabis, more research is being devoted to the long-term effects of cannabis use on brain health. Cannabis use disorder (CUD) is characterized by symptoms like psychosis and cognitive impairment, and research suggests that there might be a genetic basis to CUD susceptibility. Genome-wide association studies (GWAS) analyze genomes (genetic maps) of a large number of people to identify genetic variants (with known locations in the genome) that are associated with various diseases. Recent GWAS have led to mixed results regarding the heritability of CUD susceptibility, either failing to identify genes associated with CUD or linking different genetic variants with cannabis use. Thus, the genetic contribution to CUD risk is not entirely clear. This week in Nature Neuroscience, Demontis and colleagues conducted a GWAS to identify genetic markers associated with CUD.

How did they do it?

Genetic data of 2387 individuals with a CUD diagnosis and 48,985 individuals without CUD (controls) was obtained from iPSYCH, a database containing DNA data of a large sample of the Danish population. The genetic data included about 9 million genetic variants in the genome of each of the individuals analyzed. In a GWAS the individuals should not be related and should be similar with respect to ethnicity, which the authors carefully controlled before moving forward with the analysis. To determine if any of the variants were associated with CUD, they first performed an association analysis using logistic regression (a statistical technique) in order to see if there were any genetic variants that were overrepresented in individuals with CUD compared to controls.

In the GWAS the authors identified one place in the genome linked to increased risk of CUD. To ensure the robustness of the identified genetic risk variant, the authors evaluated the finding in genome data from a separate dataset from Iceland to see if they could replicate the finding. A polygenic risk score analysis was also conducted to determine whether the results from the two GWAS were reliable. In this analysis, all of the genetic markers associated with CUD are used to predict the risk of developing CUD. Thus, they used the risk scores calculated from genetic markers identified from the two GWAS to determine how reliably the markers are associated with CUD. They further tested the association between age at CUD diagnosis and the dosage of the identified genetic markers. Finally, they used transcriptomes containing information about gene expression in various parts of the brain to identify genes that are functionally related to CUD.

What did they find?

The authors identified one place in the genome with genetic variation significantly related to CUD, located on chromosome 8 (a result which was replicated in the independent cohort from Iceland). The polygenic risk score analysis revealed that the identified genetic markers were not related to other psychiatric disorders like schizophrenia and were specific to CUD. The authors also identified the index variant as rs56372821 in both GWAS, which is the genetic marker that is most significantly associated with CUD. This genetic marker had a risk allele and a protective allele. Interestingly, of the individuals diagnosed with CUD, those who had the risk alleles were diagnosed with CUD about one year earlier than those with the protective allele of the gene. Thus, having the protective allele of the index variant identified in these studies might result in delayed development or diagnosis of CUD. In the brain, the index variant was further related to CHRNA2 expression. The CHRNA2 gene is related to the expression of an acetylcholine receptor subunit that has previously been linked to substance dependence and abuse. When the expression of CHRNA2 was compared across individuals with CUD and controls, the authors found a reduction in CHRNA2 expression in the former group in the cerebellum, the cerebellar hemispheres, and the dorsolateral prefrontal cortex. This suggests that CHRNA2 expression may play a functional role in susceptibility to developing CUD.

What's the impact?

This study identified genetic variants associated with the risk of developing CUD using GWAS, replicating the findings in an independent sample of individuals with CUD and controls. The finding linking the index variant to CHRNA2 expression in the cerebellum is particularly interesting because there is a high concentration of cannabinoid receptors (that cannabis acts on) in the cerebellum. Thus, there might be a potential functional link between CUD and CHRNA2 expression that could be investigated by future studies.

Demontis et al. Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nature Neuroscience (2019).Access the original scientific publication here.