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Primary Psychiatry. 2009;16(8):40-46
Dr. Edwards is post-doctoral researcher in the Department of Psychiatry at Virginia Institute for Psychiatric and Behavioral Genetics; Dr. Svikis is professor in the Department of Psychology and deputy director of the Institute for Women’s Health; Dr. Pickens is professor in the Department of Psychiatry at Virginia Institute for Psychiatric and Behavioral Genetics; and Dr. Dick is assistant professor of psychiatry, psychology, and human and molecular genetics at Virginia Institute for Psychiatric and Behavioral Genetics, all at Virginia Commonwealth University in Richmond.
Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Danielle M. Dick, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Department of Psychiatry, PO Box 980126, Richmond, VA 23298-0126; Tel: 804-828-8756; Fax: 804-828-1471; E-mail: ddick@vcu.edu.
Focus Points
• Substance addictions are influenced by genetic factors and frequently co-occur.
• Various gene discovery methods have been used to identify genes influencing susceptibility to addictive disorders.
• Genetic risk loci often influence addiction to multiple substances.
• The field of pharmacogenetics is advancing our knowledge of how genetic variation influences response to pharmacologic treatment of addiction.
• In the future, the hope is that information gleaned from gene identification studies and pharmacogenetics can be used to provide more individual-specific risk assessments and tailored prevention and treatment plans.
Abstract
Addictive disorders are prevalent in many populations, influenced by genetic and environmental factors, and moderately to highly heritable. Often, addictions to different substances co-occur, and evidence from twin studies suggests that this is due, at least in part, to a common underlying genetic etiology. Techniques for gene discovery include linkage analysis, association studies of candidate genes, and genome-wide association tests. These approaches have enabled the identification of genes influencing addiction to alcohol, nicotine, and illicit substances. This article reviews recent findings of genetic loci affecting susceptibility to substance addictions. Contributions to our understanding of liability and treatment from the field of pharmacogenetics are also considered. Finally, the clinical relevance of the current state of addiction genetics is discussed.
Introduction
The social and economic costs of alcohol and other substance use disorders to our society are substantial. The Office of National Drug Control Policy estimated that in 2002, the economic costs associated with drug abuse exceeded $180 billion. This estimate took into account drug-related criminal activity as well as potential lost productivity due to disabilities and premature death.1 Sadly, while substantive, these figures fail to capture the full impact of substance use disorders not only upon the individuals themselves, but also their family members.
Addiction can take many forms, including not only substance use disorders, but also pathologic gambling, bulimia, and a host of other disorders. For the purpose of this article, discussion is limited to drug-related addictions, specifically addiction to nicotine, alcohol, or illicit drugs. Terms such as dependence, abuse, and addiction are used relatively interchangeably; however, there is ongoing debate within the field regarding the best terminology. Furthermore, differences in how these phenotypes are delimited can have an impact on the results of gene discovery efforts. Genetic loci that have been consistently associated with various forms of substance addiction, as well as those that demonstrate relevance to pharmacologic treatment, are both discussed.
Genetic Epidemiology of Addiction
Prevalence
The prevalence of addictive disorders varies across cohorts and populations. Recent estimates of lifetime alcohol abuse and dependence from the National Epidemiologic Survey on Alcohol and Related Conditions are 17.8% and 12.5% respectively, with prevalence among males nearly double that of females and wide variation across ethnic groups.2 For illicit drugs, prevalence rates are lower, but males continue to have higher rates than females. Kendler and Prescott,3 using the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, found cannabis abuse/dependence to be most prevalent (7.8% among females and 18.6% among males), followed by cocaine abuse/dependence (3.6% for females and 5.7% for males), and finally opioid abuse/dependence (0.6% for females and 2.0% for males). Nicotine dependence is more common, with 6.5% of females and 16.7% of males meeting criteria for dependence based on the Fagerstrom Test for Nicotine Dependence (FTND).
Heritability
One goal of twin studies is the estimation of a trait’s heritability in a population—that is, what proportion of phenotypic variation is due to genetic variation underlying the trait. Twin studies accomplish this by comparing phenotypic similarity between monozygotic twins, who share all of their genetic variation, with dizygotic twins, who share half of their genetic variation on average. Heritability for addictive disorders varies among substances, populations, ages, and sex. Estimates of the heritability of alcohol dependence are consistently in the range of 50% to 60%4,5 in studies of United States populations, which is comparable to European estimates using the Swedish Twin Registry. For nicotine dependence, heritability estimates vary considerably, ranging from .30–.75.3,6,7 Heritabilities in the range of .30–.60 are also observed for illicit drug dependences.8,9 Variability in the exact estimates is likely a function of age of the participants (genetic influences generally increase across development),10 cohort differences, and the exact phenotype being studied. While this article focuses on genetic influences on addiction, it is also notable that environmental influences play an important role in the development of alcohol and drug use disorders, and likely moderate the importance of genetic effects under certain circumstances.
Comorbidity
Epidemiologic studies find that individuals rarely abuse a single substance. Instead, polysubstance abuse/dependence is normative, with high rates of comorbidity across various drug classes.2,11 In addition, persons with substance use disorders also exhibit higher rates of other psychiatric disorders including depression and antisocial personality disorder. Twin studies suggest that this comorbidity is due at least in part to a shared genetic etiology underlying susceptibility to different types of substance use and/or other psychopathologies. Kendler and colleagues12 used the Virginia Twin Registry sample to identify common genetic factors underlying substance use disorders and externalizing/internalizing behavioral disorders (eg, conduct disorder, generalized anxiety disorder), and found that one common genetic factor accounted for 34% of the variance in alcohol dependence and 42% of the variance in abuse/dependence on other drugs; unsurprisingly, this factor also loaded onto adult antisocial behavior and conduct disorder. These results suggest a common genetic factor for both substance dependence/abuse and general externalizing psychopathologies (Figure). Using only male twins from the same population, Kendler and colleagues11 found that a common genetic factor loaded strongly onto abuse/dependence of all classes of illicit drugs.
Gene Identification Efforts
Evidence for significant heritability for all of the addictive disorders has led to considerable efforts to identify the specific genes involved. This has been complicated by the fact that addictive behaviors are complex genetic traits that are both phenotypically and genetically heterogeneous. It is expected that there are multiple genetic loci influencing manifestation and variation in these behaviors, and that these loci vary in the direction and magnitude of their effects. Further complicating our understanding of the genetics of addiction are interactions between loci (epistasis) and gene-by-environment interactions. Thus, although drug abuse and dependence are clearly influenced by genetic components, the genetic dissection of these disorders is more complicated than that of Mendelian traits.
Several strategies have been used to identify genes involved in addictive disorders (Table). One approach to the identification of genes influencing drug addiction is to investigate a priori candidates. For example, knowledge of the pharmacology of a given drug has been used successfully to identify genes affecting susceptibility to drug dependence via hypothesized metabolic pathways. With the increasing availability of genetic markers spread throughout the genome, more systematic approaches to gene identification have gained favor. Such studies are agnostic in their design, scanning large portions of the genome—or the entire genome—to ascertain regions that are significantly associated with the phenotype of interest. Techniques such as linkage mapping and genome-wide association studies (GWAS) are now commonly employed in the study of complex disorders such as drug use disorders, and can be applied in case-control studies or population-based studies. Using these broad methods, several genes have been identified as influencing susceptibility to addiction and are described below. Emphasis in this article is on findings for which there have been successful attempts at replication; however, there is nearly always inconsistency in the literature with regard to the effect of a given gene on a particular phenotype, including some genes described below. Although the scope of this article precludes a thorough review of inconsistencies and discussion of potential explanations for failures to replicate, it is likely that phenotypic and genetic heterogeneity, methodologic variation across samples, low power, and population stratification all contribute.
Genes Involved in Alcohol Metabolism
Several genes involved in the metabolism of alcohol have been repeatedly implicated in the development of alcohol addiction and susceptibility to dependence on other drugs. Two of these are alcohol dehydrogenase 1B (ADH1B), which is involved in the conversion of ethanol to acetaldehyde; and aldehyde dehydrogenase 2 (ALDH2), which converts acetaldehyde into acetate. Acetaldehyde is toxic and its accumulation leads to “flushing,” an unpleasant physiologic reaction involving headache, nausea, and heart palpitations. Polymorphisms in alcohol metabolism genes that affect acetaldehyde levels can have a profound impact on drinking behavior.13 For example, the ADH1B*2 allele rapidly oxidizes ethanol, and is protective against alcoholism; this effect is most evident among East Asian populations, in which the frequency of this allele is high. Individuals carrying at least one of these alleles are far less likely to develop alcoholism. Similarly, people carrying even one ALDH2*2 allele are strongly protected against alcoholism, as this allele is essentially dominant negative and carriers have severely reduced rates of acetaldehyde conversion, resulting in the experience of negative physiologic effects associated with alcohol use.14
Genes involved in alcohol metabolism have also been implicated in systematic gene identification efforts. ADH3 is an alcohol dehydrogenase gene that has been associated with alcohol dependence15 and polysubstance abuse16 in genomic linkage scans, as has ADH4).17 Kuo and colleagues,18 using the Irish Affected Sib Pair Study, found associations between alcohol dependence and multiple alcohol dehydrogenase genes, as well as ALDH2. A genome-wide linkage study in this sample has also found evidence of susceptibility loci on chromosome 4 in a region spanning several ADH genes.19
γ-Aminobutyric Acid System
The γ-aminobutyric acid (GABA) system is integral to the behavioral response to alcohol. GABAA receptors are sensitive to alcohol, and their activation can result in sedation, motor impairment, and anxiolysis; their activation might also influence response to alcohol administration through reward pathways.20 Clusters of GABAA receptors exist throughout the genome, notably on chromosomes 4, 5, and 15.21 Of particular interest is the chromosome 4 cluster as the region harboring these genes has been implicated in several linkage scans.15,22,23 Polymorphisms in two of the GABAA receptor genes, GABRA222,24,25 and GABRG1,25 subsequently have been associated with susceptibility to alcohol dependence as well as brain oscillations, an endophenotype for alcohol dependence.22,26 GABRA2 has also been associated with illicit drug dependence, antisocial personality disorder, and conduct disorder, suggesting this gene may be involved in addictions through general externalizing pathways.27
Other GABA-related genes that have been implicated in alcohol dependence are GABRA1,25,28 another GABAA receptor, and glutamate decarboxylase,29 which encodes the rate-limiting enzyme in GABA synthesis. GABRA1 was implicated in alcohol use disorders in two distinct populations, Finnish Caucasian men and Plains Indians (male and female). Polymorphisms in glutamate decarboxylase-1 are specifically associated with age-at-onset of alcohol dependence. GABRG3 is associated with alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample.30 The influence of GABAergic signaling on alcohol-related phenotypes is pervasive, making this an exciting area for future research. Interestingly, this system has also been implicated in nicotine dependence: GABRA4 was a top “hit” in a large case-control study31 that investigated >300 genes for their association with nicotine dependence as measured by the FTND.
Neuropeptide Y
Neuropeptide Y (NPY) is of interest to the field of drug abuse in part for its established role in stress response. NPY, which is expressed throughout the cortex, has anxiolytic, antidepressive, and sedative effects, which appear to act in part through the Y1 receptor.32 Binding at Y2 receptors appears to regulate emotionality.32 These effects are relevant to the development of drug abuse and dependence, as drug use might be initiated in an attempt to self-regulate symptoms of psychopathology. Initial empirical evidence for an effect of NPY on alcohol consumption came from animal models, in which it was found that NPY levels were inversely related to ethanol consumption.33 Subsequently, a variant in the NPY gene was associated with alcohol consumption in humans.34 Variants in the Y1 receptor have been associated with alcohol preference,35 NPY2R single nucleotide polymorphisms are associated with multiple dependence phenotypes,36 and NPY5R is associated with alcohol withdrawal.36
NPY-related genetic variants have also been implicated in nicotine dependence. Several receptors (NPY2R, NPY1R, and NPY5R) have been associated with dependence through linkage and/or microarray analyses.37 Although the nature of the relationship between NPY and nicotine remains unclear, work in animal models has found that NPY attenuates withdrawal symptoms,38 and that nicotine can impact the role of NPY in appetite.39
Dopamine and the Reward Pathway
Genes that are part of the dopaminergic system are considered a priori candidate genes for drug addiction, at least in part because of the role of dopamine (D) in the reward pathway.40 In particular, the D2 receptor (DRD2) has received much attention. Recently, genetic variants in DRD2 have been associated with methamphetamine dependence,41 heroin dependence,42 smoking behavior,43 alcohol dependence,44 (although Dick and colleagues45 provide results implicating neighboring gene ANKK1 in alcohol dependence, and Gelernter and colleagues46 for nicotine dependence,) and cocaine dependence,47 as well as with a myriad of non-drug related psychiatric disorders and other impulsive/addictive behavior.48 Another dopamine receptor, DRD4, has also been associated with addictive phenotypes, including opioid dependence,49 smoking behavior,50 and alcohol use.51 The dopamine transporter gene and catechol-o-methyltransferase, which degrades dopamine, have also been the focus of multiple studies on addiction. Variants in these genes have been shown to be associated with reward response,52 opiate addiction,53 and nicotine dependence.54 Although the functional effects of these polymorphisms are not all well-characterized, some have been shown to impact gene expression levels, dopaminergic tone, or sensitivity to relevant stimuli.
Nicotinic Receptors
Candidate genes for nicotine dependence are often those involved in its reception and signaling pathway. Examples include the nicotine receptors CHRNA6 and CHRNB3, in which polymorphisms have been associated with dependence on tobacco and the number of attempts made to quit, respectively.55 Variation in CHRNA5 has been associated with heaviness of smoking; these receptors have been found in both dopaminergic and GABA-ergic neurons.56 CHRNA2 has been implicated as affecting nicotine dependence through linkage, microarray results, and bioinformatics approaches37; CHRNB1 was identified as a candidate gene through linkage and subsequent associations with dependence.57 Saccone and colleagues30 found strong evidence that CHRNB3 and CHRNA5 are associated with nicotine dependence. The former had been previously implicated in a GWAS using >1,000 nicotine-dependent cases and nearly as many controls.56
CHRM2
The gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) also appears to influence different types of drug use. A genome-wide linkage analysis for alcoholism susceptibility in the COGA sample identified a linkage peak on chromosome 714 near CHRM2. This region was subsequently identified in a linkage scan for evoked response P300 oscillations (a potential endophenotype for susceptibility to alcohol dependence).58 Wang and colleagues59 performed association tests and haplotype analyses within CHRM2 and found positive results for individuals comorbid for alcohol dependence and major depressive disorder. This gene has since been associated with other types of drug dependence,60 affective disorders,60 and intelligence.61
Pharmacogenetics
The field of pharmacogenetics centers on the identification of genetic variants that influence the physiologic response to drugs, including both drugs of abuse and pharmacotherapies (such as antidepressants). One goal of the discipline is personalized medicine: that is, tailoring clinical treatment to an individual’s genomic make-up.62 With respect to addiction, it is believed that by identifying genes involved in the physiologic response to drugs of abuse, more effective pharmacotherapy can be developed. For example, the knowledge that nicotine interacts with particular receptors in the brain enables researchers to design treatments that act as receptor antagonists (or, in other cases as agonists) to block the effect of the nicotine. Different treatments might target different proteins in the relevant pathway with distinct treatment goals; for example, one treatment might reduce craving for a drug, while another reduces the rewarding effects of a drug. Knowledge of genetic variants and their potential influence on drug treatment could help clinicians determine the best treatment plan.63 Much work remains to be done in the elucidation of how variation in neurotransmission-related genes influences response to pharmacologic treatment of addiction, but recent results are quite encouraging and the pace of progress in this area is likely to increase as technologic expenses decrease. Reviewed here are some advances in pharmacogenetics that have furthered our understanding of the underlying causes of drug addiction and its treatment.
Nicotine Dependence
Candidate genes for drug response are those known to be in the pathways through which specific drugs are absorbed, transported, or metabolized. For example, the gene CYP 2A6, a member of the cytochrome P450 (CYP) family, is involved in nicotine metabolism and is therefore a promising candidate for nicotine addiction studies. Variants in CYP 2A6 influence the rate at which nicotine is metabolized,64,65 and might be related to an individual’s likelihood of success in smoking cessation.66 Similarly, an exonic variant in CYP 2B6 has been associated with variation in protein expression and with success in smoking abstinence,67 making it a potential target for pharmacologic treatment of nicotine addiction.
Opioid Dependence
In addition to their role in nicotine dependence, CYP genes have also been associated with variation in resistance to opioid dependence. Multiple family members (eg, CYP 3A4, CYP 2D6, CYP 1A2) are involved in opiate metabolism. Allelic variation in CYP 2D6 has been associated with metabolism efficiency, and individuals carrying alleles that confer less efficient metabolism appear to be protected from opioid dependence68; those who do become dependent have fewer withdrawal-related complications during methadone treatment than do their high-metabolizer counterparts.69 Furthermore, the drugs typically used to treat opiate addiction (methadone, levo-α-acetylmethadol, and buprenorphine) are all metabolized by CYP 3A4, and the efficacy of these treatments might be affected by allelic variation in this gene,70 although this hypothesis remains to be rigorously tested. Similarly, variation in the enzymes responsible for cocaine metabolism (eg, pseudocholinesterase) has been associated with differential ligand binding efficiency and catalytic activity, which might mediate individuals’ capacity for addiction to cocaine.70
Numerous studies have investigated how genetic variation in opioid receptors might influence susceptibility to opiate addiction. Polymorphisms in the μ, κ, and δ opioid receptor genes have been associated with addiction to alcohol, heroin, and cocaine,71 as have the genes encoding prodynorphin72 and proenkephalin,73 ligands in the opioid system. The μ receptor gene (OPRM1) has received much attention: it is the primary site of action for heroin and morphine, and genetic variation in OPRM1 has been associated with response to heroin,74 although there are numerous non-replications of these results.75 If such variation does influence subjective response to opiates, it might influence an individual’s vulnerability to addiction.
Alcohol Dependence
Interestingly, OPRM1 has also been associated with variation susceptibility to alcohol dependence, presumably due to the effects of ethanol on the endogenous opioid system. One polymorphism has been associated with the response to treatment of alcoholism with naltrexone,76,77 such that individuals carrying at least one Asp40 allele are less likely to relapse.
The opiate system could also impact risk of alcohol dependence through its effect on the dopaminergic system. As previously discussed, various genes in the dopamine system have been associated with different types of drug dependence. Dopamine might also be relevant in the treatment of such dependency. Indeed, variation in DRD4 has been associated with response to naltrexone,78 although this result has not yet been replicated.
Although more research is needed before personalized medicine will be possible and practical, pharmacogenetic approaches clearly have the potential to contribute a great deal to our understanding and treatment of drug and alcohol addiction disorders.
Clinical Applications
The clinical applications of addiction genetics are complicated. It is critical to convey to clients that the fact that a disorder such as alcoholism “runs in families” does not mean that only genes are responsible for its etiology—the environmental component of risk must not be ignored. Since genetic vulnerability is a function of genotypes at a large number of loci, knowing an individual’s genotype at only a few loci is insufficient for calculating their risk. Although our knowledge of the specific genes involved in addiction is not sufficiently advanced for this information to be practically used in clinical settings at the present time, the hope is that eventually information about specific genes that alter susceptibility for addictive disorders can be used to provide more individual-specific risk assessments. This information could be used to create more tailored programs for prevention and intervention. Recognizing this potential for genetic information will necessitate our understanding the pathways of risk and environmental factors that moderate risk associated with specific genetic profiles. Finally, in the future it may be possible to have pharmacotherapies tailored to patients based on their individual genetic make-up.
Conclusion
Many of the genes that have been associated with addiction appear to influence susceptibility to dependence on multiple drugs, suggesting a large portion of the genetic risk for drug use disorders is through broad, externalizing pathways. Much work remains before we can fully characterize how the genes identified thus far confer risk for drug addiction.79 Advances in genomic technologies are improving our ability to address many of the complexities associated with addictive disorders, including genes of small effect and the presence of gene-environment interaction. The future prevention and treatment of addictive disorders will hopefully benefit from the success of gene-finding techniques in conjunction with functional, developmental, and pharmacologic studies of the genes identified. PP
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