As shown in Table 1, GWAS of SUDs have included relatively more diverse samples compared to other psychiatric disorders, but the numbers of non-European samples are still well below the European-ancestry sample sizes. Candidate gene and genome-wide analyses are increasingly integrated to identify genetic variations influencing addiction. In the former, genes known to influence the pathogenesis or treatment of addictions are selected, for example, based on discoveries in animal pharmacobehavioral and genetic studies or based on what is known about the pharmacokinetics signs of being roofied and pharmacodynamics of the drug. Alcohol’s ability to enhance GABAergic neurotransmission (GABA acts as the main inhibitory neurotransmitter) is considered to be central to its rewarding effects. Specifically, recent experiments have revealed neuroadaptations in the GABAergic system that appear to be critically involved in the development of nicotine addiction.
Recent years have brought substantial progress in advancing our understanding of the genetic architecture of SUDs and other substance use behaviors (e.g. consumption quantity), and relating these findings to etiologically-relevant processes for the development of SUDs. The field will continue to see significant advances in genetic discovery as larger sample sizes of individuals of diverse ancestry begin to become realized. It is the hope that these continued advancements will have clinically meaningful implications for SUD prevention and treatment in the future. Another potential direction is the integration of human genetic data with findings from animal models of addiction endophenotypes (Reynolds et al., 2020). The substance use genetics literature is rich with rodent models of addictive behaviors (e.g. positive reinforcement via self-administration paradigms, withdrawal avoidance and drug-seeking). Despite the challenges that must be overcome to integrate human and animal genetic data (e.g. handling non-orthologous genes), rodent endophenotypes may provide insight into the neurobiological mechanisms linking genes to SUD risk.
The genetics of addiction
- Substance-specific genes include genes for metabolic enzymes (ALDH2, ADH1B) as well as genes encoding gatekeeper molecules such as drug receptors (eg, nicotinic receptors, OPRM1).
- Genetic studies have begun to elucidate the molecular mechanisms underlying SUDs and related traits, including other psychiatric conditions with which SUDs frequently co-occur (Grant et al., 2016; Kessler, 2004).
- Reflecting these diverse actions, serotonin-specific reuptake inhibitors are the most commonly prescribed category of medications for mental illness.
- Estimates of the heritability of CocUD range from ~0.40 to 0.80, with evidence of a common genetic vulnerability with other SUDs, especially cannabis, and little evidence of cocaine-specific genetic influences (Kendler et al., 2007).
- It’s increasingly common for someone to be diagnosed with a condition such as ADHD or autism as an adult.
Download, read, and order free NIMH brochures and fact sheets about mental disorders and related topics. The genetic connection to addiction comes through inherited levels of dopamine, a neurotransmitter made in your brain. Heritable factors contribute across the stages of cigarette smoking and NicUD, with a range of heritability estimates for nicotine dependence (ND) between ~0.30 and 0.70 (Agrawal et al., 2012; Sullivan & Kendler, 1999). Variability in reported h2 results for NicUD could, at least in part, be due to the different ways in which NicUD-related problems have been assessed e.g. Fagerström Tolerance Questionnaire (FTQ), Fagerström Test for Nicotine Dependence (FTND) in comparison to NicUD as determined by DSM diagnostic criteria (Cohen, Myers, & Kelly, 2002; Payne, Smith, McCracken, McSherry, & Antony, 1994).
The Genetic Basis of Addictive Disorders
Tailored interventions could include advice on exercise, diet, and sleep, and providing relapse-prevention counseling, support groups, vocational training, housing assistance, and other resources based on a patient’s specific needs and circumstances. The latest information and resources on mental disorders shared on X, Facebook, YouTube, LinkedIn, and Instagram. Take our free, 5-minute substance abuse self-assessment below if you think you or someone you love might be struggling with substance abuse. The evaluation consists of 11 yes or no questions that are intended to be used as an informational tool to assess the severity and probability of a substance use disorder. An HTR2B stop codon was linked to severe impulsive aggression, ASPD, and alcoholism, with an effect that appeared to be modulated by stress, alcohol consumption, and hormones. Unlike the MAOA stop codon, the HTR2B stop codon is recurrent, being found in at least 100,000 individuals, but population-restricted.
While there are challenges inherent in studying complex, polygenic traits such as SUDs, it is hoped that better understanding the genetic basis of risk for developing SUDs will eventually help inform SUD prevention and treatment. In this review, we cover SUD epidemiology, conclusions from twin and family studies of SUDs, and findings from more recent molecular genetic studies1; finally, we summarize the current state of the field and suggest future directions. Raymond Anton, Jr., MD is an international expert on alcohol use disorder, an addiction psychiatrist, and clinical neuroscientist, as well as researcher of genetic variants predicting treatment-response to AUD medications such as naltrexone.
Definition of SUD
They are also the harbinger of an exciting future when genetic and genomic information will be used to optimize clinical trials of new addiction medications and enhance the delivery of health care through personalized SUD prevention and treatment interventions. Compared to other genetic predictors, the genomic pattern identified here was also a more sensitive predictor of having two or more substance use disorders at once. The genomic pattern linked to general addiction risk also predicted higher risk of mental and physical illness, including psychiatric disorders, suicidal behavior, respiratory disease, heart disease, and chronic pain conditions. In children aged 9 or 10 years without any experience of substance use, these genes correlated with parental substance use and externalizing behavior. Despite divergent patterns of genetic demi moore sobriety overlap suggesting non-uniform genetic influences, it should be noted that genes influencing alcohol-metabolizing enzymes (e.g. ADH1B, ALDH2) directly affect alcohol consumption, and in turn, play a role in the risk of AUD development.
Finally, there are multiple substance classes not covered in this review, including hallucinogens, ‘club drugs’, and inhalants. These substance classes have been included in a handful of twin and family studies examining drug use, but no well-powered GWAS exist. Future GWAS efforts will be informative for alcohol and shrooms how the genetics of these additional SUDs overlap with or diverge from well-studied SUDs. Mirroring findings from twin and family studies, GWAS of CanUD have identified significant genetic overlap between CanUD and other SUDs and measures of substance use.
Fowler and Kenny (2012) present how a diverse array of genetically modified mice can be used to investigate the role of specific genes in drug responses. These include conventional knockout and knockin mice, and transgenic rodents expressing either modified proteins (alternative function or human variant) or genes with no endogenous ligand (e.g., channel rhodopsin for optogenetic stimulation or designer receptors for temporal activation with designer drugs). In another paper, Klee et al. (2012) discuss the potential value of the zebrafish for studying the role of genes in modulating acute and chronic responses to drugs of abuse, particularly in human genes that have zebrafish paralogues. Indeed, multidisciplinary evidence reveals that the deceivingly simple concept of “genetics of addiction” belies the existence of a dense array of different interwoven layers whereupon genes, developmental processes, and environmental factors interact to increase or decrease the risk for SUD (Fig. 1a).
The molecular targets of the various substances of abuse have been, for the most part, well characterized. This knowledge offers a unique opportunity for investigating how variations in these targets influence the responses to drugs of abuse. Since all substances of abuse (both legal and illegal) exert their rewarding effects by increasing dopamine (DA) in the nucleus accumbens—a central node in the brain reward circuit—genetic variations affecting the DA system have been a natural and major focus of such efforts. However, the specific pathways used by different substances of abuse to increase DA vary among drug classes. Several contributions to this special issue reflect the importance of investigating how allelic variations in each of these targets, which, by virtue of their potential to modulate dopamine and other signaling pathways, have been the focus of many candidate gene studies in SUD. Overall, twin studies predict that genes involved in vulnerability to SUDs include both substance-specific genes and genes that act on common pathways involved in addiction to different agents and propensity to other psychiatric disorders.
In individuals who are vulnerable to addiction, repetitive exposure to the agent induces long-lasting neuroadaptative changes that further promote drug-seeking behaviors and ultimately lead to persistent and uncontrolled patterns of use that constitute addiction. These neuroadaptive changes are the bases for tolerance, craving, and withdrawal and lead to a motivational shift.3 Motivation to drug-seeking behavior is initially driven by impulsivity and positive reward. Addictions are in a sense “end-stage” diagnoses because at the time diagnosis is made potentially irreversible neuroadaptative change have occurred—changes that were preventable at an early point of the trajectory of the illness.