How Genetics Influence Cannabis Use Disorder

A new study from Yale University reveals the genetic factors that contribute to the risk of developing cannabis use disorder (CUD), a condition that affects some people who use cannabis frequently and experience negative consequences. The study, published in the journal Nature Neuroscience, analyzed the genomes of more than one million people and identified several genes and gene regions that are associated with CUD. The findings may help to understand the biological mechanisms underlying CUD and to develop personalized treatments for people who struggle with cannabis addiction.

How Genetics Influence Cannabis Use Disorder
How Genetics Influence Cannabis Use Disorder

Cannabis use disorder (CUD) is a mental health condition that is characterized by a problematic pattern of cannabis use that leads to significant impairment or distress. According to the DSM-5, some of the symptoms of CUD include:

  • Using more cannabis than intended or for longer periods of time
  • Having a persistent desire or unsuccessful attempts to cut down or control cannabis use
  • Spending a lot of time obtaining, using, or recovering from cannabis use
  • Craving or having a strong desire to use cannabis
  • Failing to fulfill major obligations at work, school, or home due to cannabis use
  • Continuing to use cannabis despite having social or interpersonal problems caused or worsened by cannabis use
  • Giving up or reducing important social, occupational, or recreational activities because of cannabis use
  • Using cannabis in physically hazardous situations
  • Continuing to use cannabis despite having physical or psychological problems caused or worsened by cannabis use
  • Developing tolerance to the effects of cannabis
  • Experiencing withdrawal symptoms when stopping or reducing cannabis use

The severity of CUD is determined by the number of symptoms that a person meets, ranging from mild (2-3 symptoms) to moderate (4-5 symptoms) to severe (6 or more symptoms). CUD can cause various negative consequences for a person’s health, well-being, relationships, and functioning.

Cannabis is the most widely used illicit drug in the world, with an estimated 192 million users in 2018, according to the World Health Organization. However, not all cannabis users develop CUD. The prevalence of CUD varies depending on the population and the criteria used to define it, but it is estimated that about 9% of people who ever use cannabis will develop CUD at some point in their lives, and that this rate increases to about 17% among those who start using cannabis in adolescence. CUD is more common among men, young adults, and people who use other substances or have other mental health disorders.

What are the genetic factors that influence CUD?

CUD is a complex and multifactorial condition that is influenced by both genetic and environmental factors. Previous studies have shown that CUD has a moderate to high heritability, meaning that a substantial proportion of the variation in CUD risk among individuals can be explained by genetic differences. However, the specific genes and gene variants that contribute to CUD risk have been largely unknown.

The new study from Yale University is the largest and most comprehensive genetic analysis of CUD to date. The researchers used data from the UK Biobank and the 23andMe database, which together contain the genetic information and self-reported cannabis use data of more than one million people of European ancestry. The researchers performed a genome-wide association study (GWAS), a method that scans the entire genome for common genetic variants that are associated with a trait or a disorder. The researchers identified 35 independent genetic variants that were significantly associated with CUD, 29 of which were novel discoveries. These variants were located in 16 genes and 12 gene regions that did not contain any known genes.

The researchers also performed a gene-based association analysis, which aggregates the effects of multiple variants within the same gene, and identified 19 genes that were significantly associated with CUD, 14 of which were novel discoveries. Some of these genes are involved in neuronal development, synaptic transmission, and neurotransmitter signaling, suggesting that they may affect the brain’s response to cannabis and the development of addiction. For example, one of the genes, CADM2, encodes a protein that mediates cell adhesion and synaptic connectivity, and has been previously linked to cognitive abilities, personality traits, and substance use. Another gene, NCAM1, encodes a protein that is involved in neural development and plasticity, and has been implicated in neuropsychiatric disorders and addiction.

The researchers also performed a polygenic risk score analysis, which combines the effects of multiple genetic variants across the genome into a single score that reflects the genetic predisposition to a trait or a disorder. The researchers found that the polygenic risk score for CUD was significantly associated with CUD diagnosis, cannabis use frequency, cannabis use initiation, and cannabis use problems. The polygenic risk score for CUD also predicted CUD status in an independent sample of more than 6,000 people from the Netherlands. These results indicate that the genetic variants identified by the GWAS capture a substantial part of the genetic risk for CUD.

What are the implications of the study?

The study provides new insights into the genetic architecture and biological mechanisms of CUD, which may help to improve the prevention, diagnosis, and treatment of CUD. The study also highlights the potential of using genetic information to identify individuals who are at high risk of developing CUD and to tailor interventions to their specific needs. For example, the polygenic risk score for CUD could be used as a biomarker to screen for CUD risk and to monitor the response to treatment. Moreover, the genes and gene variants associated with CUD could be used as targets for developing new pharmacological therapies or for enhancing the efficacy of existing therapies.

The study also has some limitations that need to be considered. First, the study only included people of European ancestry, so the results may not be generalizable to other populations. Second, the study relied on self-reported cannabis use data, which may be subject to recall bias or social desirability bias. Third, the study did not account for the environmental factors that may interact with the genetic factors to influence CUD risk, such as cannabis potency, availability, or social norms. Fourth, the study did not investigate the causal relationship between the genetic variants and CUD, or the molecular mechanisms by which they affect CUD. Future studies are needed to address these issues and to replicate and extend the findings of the study.

The study is a major step forward in the understanding of the genetics of CUD, which is a prevalent and complex condition that affects millions of people worldwide. The study reveals the genetic factors that contribute to the risk of developing CUD and the biological pathways that are involved in CUD. The study also demonstrates the potential of using genetic information to improve the prevention, diagnosis, and treatment of CUD. The study may pave the way for more personalized and effective interventions for people who struggle with cannabis addiction.

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