Addiction is a psychiatric pathology related to substance use, that results in a wide range of substance-related maladaptive behaviors. The number of people addicted to psychoactive substances is currently approximately tens of millions. The exact number is difficult to estimate, as most addictive substances are illegal or illegally procured, and in some regions the access to healthcare and reporting are poor(1).
Even though there are many people exposed to potentially addictive substances (opioids, benzodiazepines as therapeutic agents) on a daily basis, most of these people do not become addicted. There are people who develop temporary tolerance but who recover after giving up the addictive substance. These observations correlate with the existence of a vulnerability to addiction which may be due to several factors: intrinsic (genotype, age, sex etc.), extrinsic (availability of the substance, socioeconomic status, entourage etc.), but also the properties of the substance (pharmacokinetics, mode of administration, psychoactive effects)(2).
The chronic and recurrent nature of addictions is mainly due to changes in the brain. Even though these changes do not occur immediately at the first contact with the addictive substance, the repeated use causes neurobiological changes that sustain the behavior and lead to addiction. Initially, addiction theories focused on the reward circuitry in the brain. More recent studies have demonstrated changes in circuits involved in behavioral conditioning, motivation and executive functions. The dopaminergic hypothesis of addiction has also been complemented by the addition of glutamate, opioid and GABAergic receptors(3,4).
The mechanism of addiction development follows a three-step process, each being linked to major neurobiological circuits:
Intoxication and binge drinking are correlated with the basal ganglia.
Withdrawal and the affective component of the amygdala and habenula.
Prefrontal cortex and insula are related to craving.
Possible genetic variants alter the susceptibility in the development of addiction and, thus, raise the question of the heritability of addiction(5).
It has been observed empirically, but also from numerous studies, a high degree of heritability of addiction. Family studies have shown clusters of addicts within families and twin studies have highlighted the importance of genetic factors in these disorders. Depending on the addictive substance, there are differences observed in these studies. For most substances, heritability is around 50%, with a maximum of 79% identified for cocaine and a minimum of 23% for opioids. These results also indicate a degree of substance specificity in terms of susceptibility to developing addictions(6).
There have been numerous attempts to determine the genes involved in the development of addiction, but studies have produced conflicting results and, thus, there are few genes clearly shown to be involved in addiction. In most cases, the genes are substance-specific and are involved in the metabolization pathways or mechanisms of action of the substance, but there are instances where common elements have been identified between different substances.
From the perspective of genetic risk factors, the most studied substance used is alcohol. Approximately 1.5% of the world’s population suffers from an alcohol use disorder (harmful use or dependence). The degree of influence of genes is estimated to be around 50%, with the remainder due to environmental factors and their interactions(1).
Variants of ADH1B, ALDH2 and ADH1C, (alcohol dehydrogenase genes), involved in alcohol metabolism have a protective role against addiction by a disulfiram-like aversive mechanism. The involvement of serotonin in the development of alcohol addiction has also been theorized. A meta-analysis of the serotonin transporter gene, SLC6A4, revealed a weak association with alcohol dependence. One candidate gene is of interest in alcohol addiction – GABRA2, variants of which are strongly correlated with alcohol dependence but also with nicotine and poly-abuse. GWAS studies complement this list with a large number of genes shown to be involved in the development of alcohol dependence: SERPINC1, GCKR, SGOL1, KLB, AUTS2, ADH, ALDH2. Mutations in the transferrin (TF) gene have been correlated with the amount of alcohol consumed(6).
The high number of genes involved in alcohol dependence leads to a high variability in the risk of developing addiction and its severity. However, even though the genotype is predisposing, environmental factors play an equally important role and can be the target of preventive measures.
Nicotine addiction has a possibly higher heritability than alcohol (more than 50%), with fewer studies on this issue. The implications of CHRNA5/CHRNA3/CHRNB4 (nicotinic receptor genes) in the development of addiction are demonstrated. In addition to these, but with inconsistent results, variants of the CHRNA4 gene impact nicotine addiction, including the maximum number of cigarettes per day. The DRD2/ANKK1 Taq1A allele, an allele studied in alcohol, is associated with smoking initiation and maintenance but not with the number of cigarettes smoked per day(8).
The first GWAS studies were conducted in the context of nicotine addiction, confirming the involvement of the aforementioned genes in the development of addiction. Moreover, associations between genes involved in nicotine dependence and other somatic pathologies have been found. As a result, variants of the CHRNA5 gene are associated with lung cancer, but also with the development of COPD and peripheral vascular pathology, known to be associated with cigarette smoking. Another association found is between the CYP2A6 gene – involved in nicotine metabolism – and lung cancer and pulmonary emphysema(7).
Indirectly, mutation in the CYP2A6 gene, causing the slow metabolizer phenotype, is associated with fewer cigarettes per day, with fewer cases of nicotine addiction and with a higher rate of smoking cessation success(7,8).
The main candidate genes for opioid addiction are those for the opioid receptors Mu and Delta (OPRM1 and OPRD1, respectively), but also DRD2 (for the dopamine D2 receptor) and BDNF (for brain-derived neurotrophic factor) genes. Variants of these genes are involved in the development of opioid addiction, but have not been shown to be equally correlated with it in different populations. In the European population, OPRD1 and DRD2 genes are more highly correlated than the others(9).
GWAS studies have brought several candidate genes into question, but there are few such studies and the results are inconclusive.
There is a paucity of genetic studies on cannabis. Thus, the results so far do not indicate anything conclusive, but bring into consideration several candidate genes for further research.
Cannabis addiction is weakly associated with variants of the cannabinoid receptor CNR1 and with FAAH, the gene for fatty acid amide hydrolase. There have been previous attempts to demonstrate links between variants of genes involved in alcoholism and cannabis dependence, but the results have been inconclusive(10).
Results from studies on cocaine addiction have implicated multiple genes in its development. Multiple single‑nucleotide polymorphisms in DRD2/ANKK1, NCAM1, TTC12, CALCYON, DBH, COMT etc. genes have been involved in addiction. However, the results have not been replicated and studies are needed to demonstrate a clear link with addiction. A polymorphism in the CHRNA5/A3/B4 cluster, also implicated in nicotine addiction, has been shown to be a protective factor for cocaine addiction and a risk factor for nicotine addiction(11).
The existing data on the remaining psychoactive substances are limited. Most of the results are inconclusive at present, but research in this area has gained considerable momentum in recent years.
The main area currently benefiting from the results obtained in addiction genetics is pharmacogenetics ,in order to tailor treatments to patients’ genotypes.
One of the first drugs targeted on addiction – disulfiram, by inhibiting aldehyde dehydrogenase and reducing ALDH2 gene expression, can be considered a drug with a pharmacogenetic mechanism(12). Another piece of information from genetic studies is the effect of naltrexone on alcohol consumption. Patients with Asp40 alleles of the OPRM1 gene (Mu 1 opioid receptor gene) have a significantly better response to this therapy.
In nicotine dependence, the replacement therapy has a better effect in rapid metabolizers. Also, slow metabolizers need a reduced dose of nicotine spray, and the response to patches is unaffected. The response to varenicline – the most effective treatment for nicotine dependence – is modified by variants in the CHRNA4 and CHRNB2 genes(13).
Last but not least, alleles of the OPRD1 (opioid receptor Delta 1) gene cause changes in the pharmacokinetics of methadone and buprenorphine administered as part of opioid substitution therapy. A variant of the ALDH5A1 gene causes nonresponse to methadone substitution treatment, therefore an alternative must be sought(14).
Genetic research in the field of addiction is at an early stage. With the exception of alcohol, the other substances have a limited body of research and the results so far are inconclusive.
The possibility of GWAS studies now open the way to potential new genes with implications for addiction, as evidenced by the plethora of candidate genes proposed for further research.
The implications of results from this area of research are not only to uncover factors influencing addiction, but also to provide the basis for new treatments or the optimization of existing ones using pharmacogenetics. Personalizing and streamlining treatments and therapeutic approaches to addictions can significantly improve their social impact.