Researchers find the genetic underpinnings of cannabis use disorder

Breaking new ground 17. nov 2020 4 min Associate professor Ditte Demontis Written by Kristian Sjøgren

Enjoying cannabis smoking is not the same as having an increased risk of cannabis use disorder. The genetic underpinnings differ, says a researcher.

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People with cannabis use disorder face many challenges in life, including mood swings, poor work performance and reduced general well-being.

Researchers estimate that genes are associated with 50–70% of the risk of cannabis use disorder, with environmental and early childhood factors comprising 30%.

Researchers in a large international study with Danish participation have now identified some of the genes influencing the progression from the first joint to lifelong use disorder. The discovery could pave the way for new diagnosis, prognosis and treatment options.

“This knowledge may enable us to better identify people who are at risk of cannabis use disorder in the long term and how we can treat them early to prevent them from developing a disorder and treat those who have already developed it,” explains Ditte Demontis, Associate Professor, Department of Biomedicine, Aarhus University, a Danish contributor to the new study.

The research results have been published in Lancet Psychiatry.

Genes may increase the risk of cannabis use disorder in several ways

Overall, two types of genetic predisposition can influence whether a person has an increased risk of cannabis use disorder.

One is related to behaviour. Examples include genes that predispose for increased risk-taking, impulsive behaviour or a desire to experiment, all of which also increase the potential of being tempted to try various psychoactive substances, including cannabis. The opposite may also apply: for example, people who are genetically predisposed to be stressed or anxious may have an increased risk of trying cannabis and then developing use disorder.

The second type of genetic predisposition is related to how cannabis affects the body, such as how various genetic variants influence the release of dopamine in the brain when using cannabis. Some people may be more impressionable in getting a kick out of smoking or eating cannabis in various ways, and this in turn increases their risk of cannabis use disorder.

However, identifying this genetic predisposition is quite complex.

“It is not the genetic variants in one gene but many genetic variants that affect the risk of developing all types of substance use disorder, each increasing the risk a little. The total quantity of genetic risk variants in our DNA determines how genetically prone we are to developing substance use disorder,” explains Ditte Demontis.

Meta-analysis included 56,000 people from Denmark

Ditte Demontis and colleagues from various countries analysed which genetic variants are associated with an increased risk of developing a cannabis use disorder. They examined the genetic profiles of 20,916 adults with cannabis use disorder versus 363,116 control adults.

Denmark provided data on 2,758 adults with cannabis use disorder and more than 53,000 control adults.

In Denmark, the researchers used the nationwide registries, including the Danish National Patient Registry and data from the Danish National Biobank at Statens Serum Institut, to identify people with cannabis use disorder and to map their genetic profiles.

“Genetics is incredibly complex, so you screen the genome for genetic variants that are associated with an increased or decreased risk of developing cannabis use disorder,” says Ditte Demontis.

Ditte Demontis also says that researchers examine such personally sensitive data under very strict data protection rules.

Cannabis use disorder and extensive use are not controlled by the same genes

The results show that two genomic locations are statistically significantly associated with an increased risk of developing a cannabis use disorder. Having either or both of these genetic variants increases your risk of developing cannabis use disorder.

“This is only the tip of the iceberg, and many other genetic variants are also involved. But they are not associated strongly enough with the risk to make this statistically significant,” says Ditte Demontis.

The second and perhaps even more interesting finding in this meta-analysis is that the genes associated with increased predisposition to use cannabis differ from the genes associated with an increased risk of developing cannabis use disorder.

A previous study showed that the genetic predisposition to drink large quantities of alcohol differs from the genetics underpinning alcohol use disorder. The new study had similar findings for cannabis use disorder.

“Until very recently, it was thought that the genetic variants associated with drinking more alcohol were also associated with an increased risk of alcohol use disorder, but studies have found that the underlying genetics only partly overlaps, and our meta-analysis is the first to show the same pattern for cannabis with only partly overlapping genetics underlying use and the diagnosed disorder” explains Ditte Demontis.

Extensive cannabis use correlated with educational attainment and low body mass index

Deeper examination of the links between genes and the use and misuse of alcohol and cannabis produces several interesting associations.

Both the previous study on alcohol and the new meta-analysis on cannabis show that the genetic variants associated with higher use of alcohol or cannabis are also linked to higher educational attainment and lower body mass index.

Conversely, some of the genetic variants associated with an increased risk of cannabis use disorder are also associated with an increased risk of low educational attainment and high body mass index.

“About 50% of the genetic variants underlying cannabis use overlap with those underlying cannabis use disorder. They do not have the other 50% in common. We also found that the genetic variants associated with cannabis use are associated with an increased number of brain fibres, whereas the genetic variants for cannabis use disorder reduce this number,” says Ditte Demontis.

Use of cannabis and social skills may be associated genetically

Ditte Demontis speculates that a third factor may link the various traits together.

Some of the common genetic variants associated with the use of alcohol or cannabis and higher educational attainment may also be associated with social skills.

“People with strong social skills may have a larger circle of friends, socialize more often and therefore also drink more often or smoke some cannabis, without this leading to use disorder, and their social relations equip them to cope with the challenges of educational attainment,” explains Ditte Demontis.

Designing medicine to counteract substance use disorder

Ditte Demontis says that the study gives researchers new insight into the biological and genetic basis of substance use disorders and that this knowledge can be used both in basic research and hopefully also in the future to help people at risk of developing these disorders.

For example, she envisions that one day people could be profiled genetically and be told whether they have a high risk of developing substance use disorder and should therefore be cautious.

Researchers may also discover more about the signalling pathways involved when people develop substance use disorder.

“This may help us to develop drugs that target these signalling pathways, thereby helping people with substance use disorder,” says Ditte Demontis.

Our research focuses on identification of genetic risk factors for externalizing childhood psychiatric disorders including ADHD and conduct disorder a...

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