A Genetic Perspective on Drug Addiction

Kate Hofbauer, 22 Nov. 2019

Today marks 4 years, 6 months, and 21 days since my brother, Jack, was picked up from the Boulder County Jail in Colorado where he had been incarcerated for 48 hours for the possession and use of illegal drugs. Between the years of 2013 to 2015, my brother’s drug use spiraled out of control and caused short-term drug induced psychological behaviors that resulted in poor decision making, impulsivity, impaired judgement, and loss of self-control. This was a result of my brother’s deadly drug addiction. Drug addiction is a chronic disease involving brain reward, motivation, and circuitry that can lead to progressive development if not treated, and it is affecting millions of people, including my brother.

Addiction is clearly defined as a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual’s life experiences. People with addiction use substances or engage in behaviors that become compulsive and often continue despite harmful consequences (American Society of Addiction Medicine, 2019). There are a wide variety of addictive agents ranging from alcohol to nicotine, drugs, foods, sex, exercise, and gambling, which create an “addictive state” in individuals that are susceptible to neurobiological overlap between pathways (Ducci & Goldman, 2012). Addiction has been a significant part of the human experience for thousands of years, that has become a worldwide epidemic affecting the lives of millions of people. To understand the evolutionary perspective of drug addiction, it is necessary to understand its significance and the genetics of the deadly brain disorder. Through the use of Twin Studies, Genome-Wide Association and Linkage Studies, and Candidate Gene Studies, the range of heritability, gene by environment interactions, and different functional variants role in initiating an addictive response in individuals has been identified.

Genetic factors have a significant impact on all steps of addiction including vulnerability to initiation, continued use, and tendency to become dependent on an addictive agent. Twin Studies have been used to determine the relative contribution of genetic and environmental factors associated with addiction. The results of Twin Studies have shown that there is a strong genetic contribution for addiction and varying heritability ranges. Additive disorders are moderately to highly heritability. For instance, alcohol abuse and dependence ranges from 50% to 70% (Ming & Margit, 2009), whereas drug use and dependence ranges from 39% for hallucinogens to 72% for cocaine (Ducci & Goldman, 2012). The heritability of addiction ranges due to a variety of factors such as sex, age, education, socioeconomic factors, and cultural background, which creates diversity in an individual’s availability and exposure to a substance. This variation in heritability is evidence that behaviors are highly influenced by functional variants and environmental factors. Additionally, Twin Studies show that in early adolescence, propensity to addiction is higher because genetic determinants are more vulnerable to addictive agents, but the vulnerability of these determinants reaches their maximum once an individual reaches young to middle adulthood.

Figure 1. Heritability ranges of 10 addictive disorders: hallucinogens, cannabis, stimulants,sedatives, opiates, cocaine dependence or abuse, alcohol dependence, smoking, caffeine consumption or heavy use, and pathological gambling computed from a large survey of adult twins (Bevilacqua & Goldman, 2009).

Identifying functional variants and loci affected by additive agents can be very challenging, but it is essential for understanding the gene by gene interactions that affect neurobiological pathways in the body when exposed to such molecules. For example, in alcoholism, the protective effects of missense variants in ADH1B (Arg48) and ALDH2 (Lys487) are additive. These variants affect consecutive steps in the alcohol metabolic pathway and moderate propensity to alcohol-induced flushing. An additive effect on risk for alcoholism along with other substance use disorders, SUDs, has been identified for functional loci mapping within the serotonin 3B receptor (HTR3B) and serotonin transporter (SLC6A4) genes (Ducci & Goldman, 2012). Additionally, there is a gene by environment interaction with this serotonin transporter promoter locus orthologous to a functional polymorphism in humans that also alters behavioral resiliency to stress, thus individuals have developed alcohol dependency as a coping mechanism during elevated periods of stress (Bevilacqua & Goldman, 2009). Furthermore, in nicotine addiction two variants associated with smoking appear to act additively. These risk variations are found in the CHRNA5–CHRNA3–CHRNB4 nicotinic acetylcholine receptor subunit cluster and in the TTC12–ANKK1–DRD2 cluster, which includes DRD2, a dopamine receptor important in nicotine reward. When adolescents carry three to four of these at risk alleles they are at higher risk of developing a nicotine addiction when exposed to the agent than the risk associated with adult individuals congruent with data presented in previous Twin Studies (Ducci & Goldman, 2012).

Genome-wide analyses and candidate gene studies have been increasingly integrated to identify genetic variations influencing addiction. Whole-genome wide association and linkage studies map a genome to determine disease causing-loci within a genome. Whole-genome wide linage studies have been used for family-based samples to test the significance of polymorphisms and meiotic linkage to a disease that may occur more frequently on chromosomes that are found in phenotypically concordant relatives than discordant relatives. This has been helpful in detecting the effects of uncommon and rare alleles. Conversely, whole-genome wide association studies have been used to identify more common alleles and their effect on more localized chromosome regions. This has led to the identification of specific gene targets for addiction through the use of intermediate phenotypes (Ducci & Goldman, 2012).

Intermediate phenotypes are quantitative biological traits that are highly heritable and show greater prevalence in unaffected relatives than in the general population. These include stress resiliency and externalizing behaviors such as disinhibition, aggression, and impulsivity, which are thought to be underlying factors that may lead to addiction and other psychiatric diseases. Intermediate phenotypes bridge the gap between target identification captured from candidate gene studies and genome-wide analyses, and help identify functional alleles that alter drug response. As previously mentioned, functional alleles can alter drug metabolism and drug receptors. By identifying the genes that are associated with functional alleles, mutational affects that alter gene expression, brain structure and function, and behavior can be known. For example, substance-specific genes have been identified to include genes for metabolic enzymes such as ALDH2 and ADH1B for alcoholism, and drug receptors such as OPRMI for nicotine addiction. Genes involved in impulsivity and reward such as monoamine oxidase A (MAOA) and serotonin transporter (SLC6A4) also show a genetic link between addictions and other psychiatric diseases when functional variants arise (Ducci & Goldman, 2012). Genome-wide association analyses have only been applied to very small addiction samples, thus less than 95% of genetic determinants have been identified, indicating many genetic risk factors for addiction have not yet been accounted for and much research still needs to be conducted. But, with the current knowledge that has been shared, the genome’s role in neuroadaptation to drugs and the ways in which genetic variations and environmental exposures interact to lead to neuronal molecular changes integral to the vulnerability to addictions and to the processes of addiction and recovery has been identified and is currently being utilized (Bevilacqua & Goldman, 2009).

Addiction is a common, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual’s life experiences that develop through multistep processes. The impact of drugs on morbidity and mortality is very high, and action must be taken to help mitigate the progressiveness of this deadly disease. As previously mentioned, twin studies highlight the heritability of addiction ranges from 50% to 70% for alcohol to 39% for hallucinogens to 72% for cocaine abuse and dependence. Twin studies reveal that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are, by definition, the result of gene by environment interactions. Gene discovery is being facilitated by a variety of powerful approaches such as genome-wide analyses and candidate gene studies. The genes that have been discovered thus far act in a variety of ways via alter drug metabolism, receptor function, and mechanisms of circuitry for reward. Genetic studies are being used to aid in addiction medicine research, and are strengthening the case for a neurobiological origin of addictive behavior. Identification of genetic determinants in addiction is very important to improve the ability to predict risk and treatment response, as well as develop new treatments and better understand the effects of the environmental on an individual’s susceptibility to addiction. It is my hope that by providing a genetic perspective on the nature of addiction, thus those suffering from this deadly brain disease can receive insight into the nature of their disorder and the origins of its roots, which will help foster a path of recovery and life of normalcy. On May 28th, 2020, my brother, Jack, will receive his fifth year chip for sobriety. To that, I am extremely grateful, inspired, and blessed. There is hope for those suffering, and change can be made with increased knowledge and understanding of this disease.

References

1. Al, Leshner. “Addiction Is a Brain Disease, and It Matters.” National Institute of Health, vol. 45, no. 7, 3 Oct. 1997. PubMed.gov.
2. Bevilacqua, L, and D Goldman. “Genes and addictions.” Clinical pharmacology and therapeutics vol. 85,4 (2009): 359–61. doi:10.1038/clpt.2009.6
3. “Definition of Addiction.” American Society of Addiction Medicine, American Society of Addiction Medicine, 15 Sept. 2019, www.asam.org/docs/default-source/quality-science/asam's-2019-definition-of-addiction-(1).pdf?sfvrsn=b8b64fc2_2.
4. Ducci, Francesca, and David Goldman. “The genetic basis of addictive disorders.” ThePsychiatric clinics of North America vol. 35,2 (2012): 495–519. doi:10.1016/j.psc.2012.03.010