Genomics: Insight

Introduction

The results from genome-wide association studies and drug and alcohol surveys indicate a role for CHRNA2 gene and specific environmental factors in the manifestation of cannabis use disorder.

Significance

After the federal government passed the 2018 Farm Bill, cannabis availability spread throughout the United States of America, leading to the discussion of cannabis use disorder (Hudak, 2018). The discussion commenced because cannabis use disorder causes vulnerability for addiction to other substances, increasing “deaths of despair”. Princeton economists Anne Case and Angus Deaton coined the phrase “deaths of despair” when they learned that the fastest rising death rates among lower socioeconomic class Americans were from drug overdoses, suicide, and alcoholic liver disease (Case & Deaton, 2020). Even though the majority of cannabis users do not go on to use harder drugs, the combination of social environments and cannabis, along with alcohol and nicotine, can prime the brain for enhanced response to other drugs. (Volkow, 2020). “A twin study of early cannabis use and the subsequent use and abuse/dependence of other illicit drugs” details the correlation between cannabis use and dependence of other illicit drugs. Using twin data as a population sample, the authors examined the association between early cannabis use and the dependence of other illicit drugs by calculating the odds ratio. The odds ratio measures whether an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. An odds ratio of 1 means exposure does not affect the odds of the outcome, greater than 1 implies the exposure correlates with higher odds of the outcome, and less than 1 means the exposure is associated with lower odds of the outcome (Szumilas, 2010, p. 227). Early cannabis use was heavily associated with other illicit drug dependence with an odds ratio of 4.8 (Agrawal et al., 2004, p. 1231). Due to early cannabis use strongly correlating with more dangerous drug dependence, cannabis indirectly produces increased deaths of despair because dangerous drugs can cause overdoses.  Case and Deaton’s paper on mortality among white non-Hispanic Americans shows an increase in mortality from suicide and drug or alcohol poisonings in three groups, but the group with the least education had mortality rates from poisonings rise more than fourfold, from 13.7 to 58.0 (Case & Deaton, 2015, p. 15080). To differentiate between suicides and poisonings, the paper places drug and alcohol poisonings as a more prominent factor to mortality rates than suicides (Case & Deaton, 2015, p. 15080). Therefore, understanding cannabis addiction remains a crucial step in diminishing the mortality rates of the less educated lower class.

Drug experts often classify cannabis as a gateway drug since cannabis opens the door to drug abuse of more dangerous drugs like heroin or cocaine

The CHRNA2 Gene

Cannabis use disorder is linked to the underexpression of the CHRNA2 gene. Expressed in the brain’s cerebellum, CHRNA2 encodes the neuronal acetylcholine receptor to mediate fast neurotransmission in the central and peripheral nervous systems (Demontis et al., 2019, p. 3). The risk variant for cannabis use disorder, rs56372821, located on an intergenic (between genes, non-coding) region on chromosome 8, contains an odds ratio of 0.73 with respect to the minor allele A in the study (Demontis et al., 2019, p. 8).  The rs56372821 is a single nucleotide polymorphism which is a gene variation at a single position in a DNA sequence.

Expressed in the brain’s cerebellum, CHRNA2 encodes the neuronal acetylcholine receptor to mediate fast neurotransmission in the central and peripheral nervous systems

The paper “​​Genome-wide association study implicates CHRNA2 in cannabis use disorder” uses whole-genome sequencing from its study of 2,387 cases of cannabis use disorder and 48,985 controls, and utilized a separate independent study, concluding that the most strongly associated variant in cannabis use disorder is rs56372821 (Demontis et al., 2019, p. 2). A P-value of 5x10-8 is required to pass genome-wide significance, with a P-value of 3.27x10−3 in the independent study cohort. However, in the meta-analysis of both studies, rs56372821 showed a stronger association (P=9.09x10−12) with cannabis use disorder (Demontis et al., 2019, p. 27). The same paper models the association of CHRNA2 expression with cannabis use disorder in three brain tissues, revealing the gene was underexpressed in cannabis users versus controls. The CHRNA2 expression model included 47 single nucleotide polymorphisms (Demontis et al., 2019, p. 25). The found underexpression of CHRNA2 in people with cannabis use disorder also possessed slower neurotransmissions in the nervous systems. 

Specific Outside Environmental Factors

Although cannabis use arises from various factors, the most crucial are peer group influence and availability because the timing of peer influence directly affects adolescent substance use, and teenage substance use is the most common factor in addiction. The paper “Impact of environmental factors on marijuana use in 11 European countries” depicts how specific factors influence cannabis use. Cannabis availability was strongly associated with frequent marijuana use in 4 countries. The highest was in Slovenia, with an odds ratio of 19.28 for boys and 19.05 for girls. The use of cannabis among peers heavily correlated with frequent marijuana use in 5 countries. The highest was an odds ratio of 23.91 for boys in Norway and 75.42 for girls in Denmark. Cannabis use among peers also correlated with early cannabis use in 8 countries for boys, with the highest odds ratio of 54.03 in Norway, and three countries for girls, with the highest odds ratio of 7.29 in Denmark (Pejnović franelić et al., 2011, p. 446). Due to the correlation between peer use and early use, the age of exposure directly affects dependency on the drug.

Because of the correlation between peer use and early use, the age of exposure directly affects dependency on the drug

The paper “Cannabis Use in Adolescence and Young Adulthood” presents information on different periods of cannabis introduction and future use. It separated the adolescent phase into two sections: mid-school (average 14.9-15.9 years) and late-school (average 16.4-17.4 years). The frequency of teenage cannabis use varied within each individual, but 82% of adolescents reporting mid-school use also reported use into the late-school period. Antisocial behavior, cigarette smoking, frequent and high-risk alcohol drinking, and the degree of peer involvement in regular cannabis use were all associated with mid-school use and late-school use (Coffey & Patton, 2016, p. 319). Cannabis dependence, more common in males, reached its peak at 20 years. In another study, researchers found that 12% of adults were diagnosed with cannabis use disorder at least once from age 20 to 35 years (Coffey & Patton, 2016, p. 319). Cannabis use disorder primarily arises from the underexpression of CHRNA2 combined with exposure to cannabis early on in life, and the age of dependence decreases as the peer exposure period unfolds earlier.

Conclusion

Even though the underexpression of CHRNA2 is connected to cannabis use disorder, not everyone that under-expresses the gene will have the disorder. Cannabis use disorder is an example of how genes and environmental factors interact in complex ways to influence expression of a disorder. Nevertheless, the role of CHRNA2 expression and environmental factors on cannabis use disorder could be used to better inform diagnosis and prevention strategies. Studying the genetic and environmental basis of cannabis addiction can save future victims of drug addiction from death. Understanding the influence of environmental factors aids in the institution of prevention strategies, such as programs that target people at the prime age of cannabis exposure, with emphasis on those of lower socioeconomic status. The understanding of cannabis use disorder is important for high school students because the majority of cannabis exposure and use occurs near the age of high school. By giving high school students an understanding of the drug and the drug’s effects, as opposed to teaching the restriction of the drug, efficiency of substance control among adolescents increases. Understanding cannabis use disorder remains a critical step in preventing unnecessary deaths to drugs and the treatment of the disease.

Cannabis use disorder is an example of how genes and environmental factors interact in complex ways to influence expression of a disorder

References

1. Agrawal, A., Neale, M. C., Prescott, C. A., & Kendler, K. S. (2004). A twin study of early cannabis use and subsequent use and abuse/dependence of other illicit drugs. Psychological Medicine, 34(7), 1227-1237. https://doi.org/10.1017/S0033291704002545
2. Case, A., & Deaton, A. (2015). Rising morbidity and mortality in midlife among white non-Hispanic americans in the 21st century. Proceedings of the National Academy of Sciences, 112(49), 15078-15083. https://doi.org/10.1073/pnas.1518393112
3. Case, A., & Deaton, A. (2020). Deaths of despair and the future of capitalism. Princeton University Press.
4. Coffey, C., & Patton, G. C. (2016). Cannabis use in adolescence and young adulthood. The Canadian Journal of Psychiatry, 61(6), 318-327. https://doi.org/10.1177/0706743716645289
5. Demontis, D., Rajagopal, V. M., Thorgeirsson, T. E., Als, T. D., Grove, J., Leppälä, K., Gudbjartsson, D. F., Pallesen, J., Hjorthøj, C., Reginsson, G. W., Tyrfingsson, T., Runarsdottir, V., Qvist, P., Christensen, J. H., Bybjerg-grauholm, J., Bækvad-hansen, M., Huckins, L. M., Stahl, E. A., Timmermann, A., . . . Nyegaard, M. (2019). Genome-wide association study implicates chrna2 in cannabis use disorder. Nature Neuroscience, 22(7), 1066-1074. https://doi.org/10.1038/s41593-019-0416-1
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7. Pejnović franelić, I., Kuzman, M., Pavić Šimetin, I., & Kern, J. (2011). Impact of environmental factors on marijuana use in 11 european countries. Croatian Medical Journal, 52(4), 446-457. https://doi.org/10.3325/cmj.2011.52.446
8. Szumilas M. (2010). Explaining odds ratios. Journal of the Canadian Academy of Child and Adolescent Psychiatry, 19(3), 227–229.
9. Volkow, N. D. (2020, July). Is marijuana a gateway drug? (Marijuana Research Report). National Institute on Drug Abuse.