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The Genetics of and Other Dependence

Danielle M. Dick, Ph.D., and Arpana Agrawal, Ph.D.

Alcohol dependence and dependence on other frequently co-occur, and strong evidence suggests that both disorders are, at least in part, influenced by genetic factors. Indeed, studies using twins suggest that the overlap between dependence on alcohol and on other drugs largely results from shared genetic factors. This common genetic liability, which also extends to antisocial behavior, has been conceptualized as a general predisposition toward a variety of forms of characterized by disinhibited behavior (i.e., externalizing psychopathology). Accordingly, many of the genetic factors affecting risk for dependence on alcohol or other drugs appear to act through a general externalizing factor; however, other genetic factors appear to be specific to a certain disorder. In recent years, researchers have identified numerous as affecting risk for dependence on alcohol and other drugs. These include genes involved in alcohol as well as in the transmission of nerve cell signals and modulation of nerve cell activity (i.e., γ-aminobutyric acid [GABA] and acetylcholinergic and the endogenous and systems). KEY WORDS: Alcohol and other drug (AOD) dependence (AODD); co-morbid AOD dependence; genetics and heredity; genetic theory of AODD; genetic risk factors; AODR genetic markers

his article explores the hypothe­ Genetic of Lynskey 2006; Kendler et al. 2003a; sis that certain genetic factors AOD Dependence Tsuang et al. 2001). Twin studies also can be used to T increase a person’s risk of both frequently co- assess the extent to which the co­ and dependence and occurs with dependence on illicit occurrence of disorders is influenced other drug abuse and dependence. It drugs (Hasin et al. 2007). Both alco- by genetic and/or environmental first reviews the evidence suggesting hol use disorders (i.e., alcohol abuse factors. Thus, a finding that the cor- that certain genetic factors contribute and alcohol dependence) and drug relation between alcohol dependence to the development of alcohol and use disorders (drug abuse and drug in twin 1 and drug dependence in other drug (AOD) use disorders, as well dependence) are influenced by several twin 2 is higher for identical (i.e., as to the development of a variety of factors. For example, family, twin, monozygotic) twins, who share 100 and adoption studies1 have convinc­ forms of externalizing psychopathol­ ingly demonstrated that genes con- 1 For a definition of these and other terms, see the glos­ ogy—that is, psychiatric disorders char- tribute to the development of alcohol sary, pp. 177–179. acterized by disinhibited behavior, such dependence, with heritability esti­ as antisocial personality disorder, atten- mates ranging from 50 to 60 percent DANIELLE M. DICK, PH.D., is an assis­ tion deficit/hyperactivity disorder, and for both men and women (McGue tant professor of , , conduct disorder. After summarizing 1999). Dependence on illicit drugs and genetics at the Virginia the difficulties associated with, and only more recently has been investi- Institute for Psychiatric and Behavioral recent progress made in, the identifica­ gated in twin samples, but several Genetics, Virginia Commonwealth studies now suggest that illicit drug University, Richmond, Virginia. tion of specific genes associated with abuse and dependence also are under AOD dependence, the article then dis- significant genetic influence. In these ARPANA AGRAWAL, PH.D., is a research cusses evidence that implicates several studies of adult samples, heritability assistant professor in the Department of genes in a person’s risk for dependence estimates ranged from 45 to 79 per- Psychiatry, Washington University, St. on both alcohol and illicit drugs. cent (for reviews, see Agrawal and Louis, Missouri.

Vol. 31, No. 2, 2008 111 percent of their genes, than for frater­ unaffected children of these people. including other forms of drug depen­ nal (i.e., dizygotic) twins, who share These findings suggest that electro­ dence, childhood externalizing disor­ on average only 50 percent of their physiological measurements can be ders, and adult antisocial personality genes, indicates that shared genes used as markers of a genetic vulnera­ disorder, again suggesting a shared influence the risk of both alcohol bility to externalizing disorders. underlying predisposition to multiple and drug dependence. The twin studies One commonly measured electro­ forms of AOD dependence and other conducted to date support the role physiological characteristic is the externalizing problems (Hicks et al. of such shared genetic factors. For so-called P3 component of an event- 2007).2 example, in the largest twin study related potential—that is, a spike in Interestingly, electrophysiological of the factors underlying psychiatric activity that occurs about 300 abnormalities are most pronounced disorders, Kendler and colleagues milliseconds after a person is exposed in alcohol-dependent people who also (2003b) analyzed data from the to a sudden stimulus (e.g., a sound or have a diagnosis of illicit drug abuse Virginia Twin Registry and found light). Researchers have observed that or dependence (Malone et al. 2001). that a common genetic factor con­ the amplitude of the P3 component tributed to the total variance in This observation is consistent with is reduced in alcohol-dependent peo­ data from twin and family studies alcohol dependence, illicit drug abuse ple and their children, suggesting and dependence, conduct disorder, suggesting that co-morbid depen­ that this abnormality is a marker for dence on alcohol and another drug and adult antisocial behavior. This a genetic predisposition to alcohol pattern also has been identified in represents a more severe disorder with dependence (Porjesz et al. 1995). several other independent twin stud­ higher heritability than dependence However, the abnormal P3 response ies (Krueger et al. 2002; Young et al. is not specific to alcohol dependence 2000). Taken together, these findings 2 Abnormalities in the P3 response also have been asso­ but appears to be associated with a suggest that a significant portion ciated with risk for other psychiatric disorders, such as of the genetic influence on alcohol variety of disinhibitory disorders, (van der Stelt et al. 2004). dependence and drug dependence is through a general predisposition toward externalizing disorders, which may manifest in different ways (e.g., different forms of AOD dependence Genes and/or antisocial behavior) (see figure). influencing However, some evidence also suggests externalizing that disorder-specific genetic influences psychopathy contribute to AOD dependence (Kendler et al. 2003b). These specific influences likely reflect the actions of genes that are involved in the metabolism of individual drugs. The idea that alcohol and drug dependence share a genetic liability Antisocial Alcohol Drug Conduct personalty with each other, as well as with other dependence dependence disorder forms of externalizing psychopathology, disorder is further supported by electrophysio­ logical studies recording the brain’s electrical activity. These studies, which are conducted using electrodes placed Disorder- Disorder- on the person’s scalp, provide a non­ specific specific invasive, sensitive method of measur­ genes genes ing brain function in . They generate a predictable pattern in the height (i.e., amplitude) and rate (i.e., frequency) of brain waves that can Figure Schematic representation of a model to illustrate the influence of genetic show characteristic abnormalities in factors on the development of alcohol dependence, dependence on other drugs, and other externalizing disorders (e.g., conduct disorder or antiso­ people with certain types of brain cial personality disorder). Some of the proposed genetic factors are dysfunction. For example, electro­ thought to have a general influence on all types of externalizing condi­ physiological abnormalities have been tions, whereas others are thought to have a disorder-specific influence. observed in people with a variety of externalizing disorders as well as in

112 Alcohol Research &

Genetics of AOD Dependence on one drug alone (Johnson et al. HapMap Project,3 and other govern­ to address questions about the nature 1996; Pickens et al. 1995). This con­ ment and privately funded efforts, of genetic influences on AOD depen­ clusion also appears to be supported have made a wealth of information dence, as discussed below. by new studies exploring the roles of on variations in the More recently, additional studies specific genes, which are discussed publicly available. Third, these devel­ have been initiated that specifically later in this article. opments have been complemented by seek to identify genes contributing advances in the statistical analysis of to various forms of illicit drug depen­ genetic data. dence as well as general drug use Identifying Specific Several large collaborative projects problems (for more information, Genes Related to AOD that strive to identify genes involved see http://www.nida.nih.gov/about/ Dependence in AOD dependence currently are organization/Genetics/consortium/index. underway. The first large-scale project html). Through these combined With robust evidence indicating that aimed at identifying genes contribut­ approaches, researchers should be genes influence both alcohol depen­ ing to alcohol dependence was the able to identify both genes with drug- dence and dependence on illicit National Institute on Alcohol Abuse specific effects and genes with more drugs, efforts now are underway to and (NIAAA)-sponsored general effects on drug use. The identify specific genes involved in the Collaborative Study on the Genetics following sections focus on several development of these disorders. This of Alcoholism (COGA), which was groups of genes that have been iden­ identification, however, is complicated initiated in 1989. This study, which tified by these research efforts and by many factors. For example, numer­ involves collaboration of investigators which have been implicated in affecting ous genes are thought to contribute at several sites in the , risk for dependence on both alcohol to a person’s susceptibility to alcohol examines families with several alcohol- and illicit drugs. and/or drug dependence, and affected dependent members who were recruit­ people may carry different combina­ ed from treatment centers across the tions of those genes. Additionally, Genes Encoding Involved United States. This study has been in Alcohol Metabolism environmental influences have an joined by several other identifi­ impact on substance use, as does gene– cation studies focusing on families The genes that have been associated environment (Heath et al. affected with alcohol dependence, with alcohol dependence most consis­ 2002). Finally, the manifestation of AOD including the following: tently are those encoding the dependence varies greatly among affected that metabolize alcohol (chemically people, for example, with respect to known as ). The main path­ age of onset of problems, types of • A sample of Southwestern American way of alcohol metabolism involves symptoms exhibited (i.e., symptomat­ Indians (Long et al. 1998); two steps. In the first step, ethanol ic profile), substance use history, and is converted into the toxic intermedi­ presence of co-morbid disorders. • The Irish Affected Sib Pair Study of ate ; this step is mediated Despite the complications mentioned Alcohol Dependence (Prescott et al. by the (ADH) above, the rapid growth in research 2005a); enzymes. In a second step, the technologies for gene identification in acetaldehyde is further broken down recent years has led to a concomitant • A population of Mission Indians into and by the actions increase in exciting results. After suf­ (Ehlers et al. 2004); of dehydrogenase (ALDH) fering many disappointments in early enzymes. The genes that encode the attempts to identify genes involved • A sample of densely affected fami­ ADH and ALDH enzymes exist in in complex behavioral outcomes (i.e., lies collected in the Pittsburgh area several variants (i.e., ) that are ), researchers now are fre­ (Hill et al. 2004); and characterized by variations (i.e., poly­ quently succeeding in identifying morphisms) in the sequence of the genes that help determine a variety • An ongoing data collection from DNA building blocks. One impor­ of clinical phenotypes. These advances alcohol-dependent individuals in tant group of ADH enzymes are have been made possible by several Australia. the ADH class I isozymes ADH1A, factors. First, advances in technologies ADH1B, and ADH1C. For both to identify a person’s genetic makeup Importantly, most of these projects (i.e., genotyping technology) have include comprehensive psychiatric dramatically lowered the cost of geno­ interviews that focus not only on 3 The International HapMap Project is a multicountry effort to identify and catalog genetic similarities and differences in typing, allowing for high-throughput alcohol use and alcohol use disorders human beings by comparing the genetic sequences of dif­ analyses of the entire genome. Second, but which also allow researchers to ferent individuals in order to identify chromosomal regions the completion of several large-scale collect information about other drug where genetic variants are shared. Using the information obtained in the HapMap Project, researchers will be able research endeavors, such as the Human use and dependence. This compre­ to find genes that affect health, , and individual Genome Project, the International hensive approach permits researchers responses to and environmental factors.

Vol. 31, No. 2, 2008 113 the genes encoding ADH1B and More recent evidence suggests that on alcohol’s with the those encoding ADH1C, several alle­ genetic variants in the ADH1A, GABA system has focused on the les resulting in altered proteins have ADH1B, ADH1C, ADH5, ADH6, GABAA . This receptor also is been identified, and the proteins encod­ and ADH7 genes are associated with the site of action for several medica­ ed by some of these alleles exhibit illicit drug dependence and that this tions that frequently are misused and particularly high enzymatic activity in association is not purely attributable have high addictive potential, such as laboratory experiments (i.e., in vitro) to co-morbid alcohol dependence , , opi­ (Edenberg 2007). This suggests that (Luo et al. 2007). The mechanism by ates, α-hydroxybutyrates, and other in people carrying these alleles, ethanol which these genes may affect risk for – compounds. is more rapidly converted to acetalde­ illicit drug dependence is not entirely Accordingly, this receptor likely is hyde.4 Several studies have reported clear. However, other observations5 involved in dependence on these lower frequencies of both the ADH1B*2 also indicate that enzymes involved drugs as well (Orser 2006). and ADH1C*1 alleles, which encode in alcohol metabolism may contribute The GABAA receptor is composed some of the more active proteins, to illicit drug dependence via path­ of five subunits that are encoded by among alcoholics than among non- ways that currently are unknown but numerous genes, most of which are alcoholics in a variety of East Asian independent of alcohol metabolism located in clusters. Thus, chromo­ populations (e.g., Shen et al. 1997) (Luo et al. 2007). some 4 contains a cluster comprising and, more recently, in European pop­ the genes GABRA2, GABRA4, GABRB1, ulations (Neumark et al. 1998; Genes Encoding Proteins Involved and GABRG1; 5 contains Whitfield et al. 1998). in Neurotransmission GABRA1, GABRA6, GABRB2, and In addition, genome-wide screens AODs exert their behavioral effects in GABRG2; and chromosome 15 contains to identify genes linked to alcoholism GABRA5, GABRB3, and GABRG3 and alcohol-related traits have been part by altering the transmission of signals among nerve cells (i.e., neu­ (see http:// www.ncbi.nlm.nih.gov/sites/ conducted in three independent sam­ ?db=gene). ples consisting largely of people of rons) in the brain. This transmission is mediated by chemical messengers Interest in the GABAA receptor European descent—the COGA study genes on grew when (Saccone et al. 2000), the Irish Affected (i.e., ) that are released by the signal-emitting neu­ this region consistently was identified Sib Pair Study of Alcohol Dependence in genome-wide scans looking for (Prescott et al. 2005a), and an ron and bind to specific proteins (i.e., receptors) on the signal-receiving linkage with alcohol dependence Australian sample (Birley et al. 2005). (Long et al. 1998; Williams et al. These studies have found evidence neuron. AODs influence the activities of several systems, 1999). Subsequently, COGA investi­ that a region on chromosome 4 con­ gators systematically evaluated short taining the ADH gene cluster shows including those involving the neuro­ DNA segments of known location linkage to the phenotypes studied. transmitters γ-aminobutyric acid (i.e., genetic markers) that were situ­ This cluster contains, in addition (GABA), , and , ated in the GABA receptor gene to the genes encoding ADH class I as well as naturally produced com­ A cluster on chromosome 4. These isozymes, the genes ADH4, ADH5, pounds that structurally resemble opi­ ADH6, and ADH7, which encode oids and . Accordingly, studies found that a significant associ­ other ADH enzymes. Polymorphisms certain genes encoding components ation existed between multiple SNPs exist for each of these genes, some of of these neurotransmitter systems may in the GABRA2 gene and alcohol which also have been associated with contribute to the risk of both alcohol dependence (Edenberg et al. 2004). alcohol dependence (Edenberg et al. dependence and illicit drug dependence. This association has been replicated 2006; Luo et al. 2006a,b; Prescott et in multiple independent samples (Covault et al. 2004; Fehr et al. 2006; al. 2005b). Genes Encoding the GABAA Receptor. Interestingly, the effects of these GABA is the major inhibitory neuro­ Lappalainen et al. 2005; Soyka genes do not appear to be limited transmitter in the human central 2007). In addition, the same SNPs in to alcohol dependence. One study —that is, it affects the GABRA2 gene have been shown to compared the frequency of alleles that neurons in a way that reduces their be associated with drug dependence in differed in only one DNA building activity. Several lines of evidence sug­ both adults and adolescents (Dick et block (i.e., single poly­ gest that GABA is involved in many 4 Rapid acetaldehyde production can lead to acetaldehyde morphisms [SNPs]) throughout the of the behavioral effects of alcohol, accumulation in the body, which results in highly unpleas­ genome between people with histories including motor incoordination, ant effects, such as , , and rapid heartbeat, of illicit drug use and/or dependence reduction (i.e., anxiolysis), that may deter people from drinking more alcohol. and unrelated control participants. , withdrawal signs, and pref­ 5 For example, the , which inhibits This study detected a significant dif­ erence for alcohol (Grobin et al. another involved in alcohol metabolism called 2 (ALDH2) and is used for ference for a SNP located near the 1998). GABA interacts with several treatment of alcoholism, has demonstrated a treatment ADH gene cluster (Uhl et al. 2001). receptors, and much of the research effect in dependence (Luo et al. 2007).

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Genetics of AOD Dependence al. 2006a), as well as with the use of One of the receptors through which has centered mainly on a gene called multiple drugs in another independent acetylcholine acts is encoded by a OPRM1, which encodes one type of sample (Drgon et al. 2006). gene called CHRM2. In the COGA (i.e., the µ-opioid Variations in the GABRA2 gene sample, linkage was observed between receptor), although the results so far are associated not only with AOD a region on that con­ have been equivocal. This gene con­ dependence but also with certain tains the CHRM2 gene and alcohol tains a resulting in a electrophysiological characteristics dependence, and subsequent experi­ different product (i.e., a non- (i.e., endophenotypes) in the COGA ments confirmed that an association synonymous polymorphism) that in sample (Edenberg et al. 2004). As existed between alcohol dependence one study was found to bind one of reviewed above, these electrophysio­ and the CHRM2 gene (Wang et al. the endogenous (i.e., β-endor­ logical characteristics are not unique 2004). This association has been repli­ phin) three times as strongly as the to alcohol dependence but also are cated in a large independent study (Luo main variant of the gene (Bond et al. found in individuals with other forms et al. 2005) that also found evidence 1998); other studies, however, could of externalizing psychopathology. that the gene was associated with drug not confirm this finding (Befort et al. This association supports the hypoth­ dependence. 2001; Beyer et al. 2004). esis that the GABRA2 gene generally As with the GABRA2 gene described Laboratory studies have suggested is involved in AOD use and/or above, the association between CHRM2 that OPRM1 is associated with sensi­ externalizing problems. Interestingly, and alcohol dependence in the COGA tivity to the effects of alcohol (Ray subsequent analyses investigating the sample was strongest in people who and Hutchison 2004). In addition, role of GABRA2 in drug dependence had co-morbid AOD dependence several studies have reported evidence (Agrawal et al. 2006) found that (Dick et al. 2007). Additional analy­ of an association between OPRM1 the association with GABRA2 was ses in the COGA sample have sug­ and drug dependence (e.g., Bart et al. strongest in people with co-morbid gested that CHRM2 is associated 2005). Other studies, however, have AOD dependence, with no evidence with a generally increased risk of failed to find such an association of association in people who were externalizing disorders, including (e.g., Bergen et al. 1997), and a com­ only alcohol dependent. This obser­ symptoms of alcohol dependence and bined analysis of several studies (i.e., vation supports the assertion that drug dependence (Dick et al. 2008). a meta-analysis) concluded that no co-morbid AOD dependence may This potential role of CHRM2 in association exists between the most represent a more severe, genetically contributing to the general liability of commonly studied polymor­ influenced form of the disorder. AOD use and externalizing disorders OPRM1 phism and drug dependence (Arias et Several other GABAA receptor genes is further supported by findings that have yielded more modest evidence CHRM2, like GABRA2, also is associ­ al. 2006). However, this finding does of association with different aspects ated with certain electrophysiological not preclude the possibility that other of AOD dependence. Thus, GABRB3 endophenotypes (Jones et al. 2004). genetic variants in OPRM1 and/or (Noble et al. 1998) and GABRG3 other genes related to the endogenous (Dick et al. 2004) are modestly asso­ Genes Involved in the Endogenous opioid system are involved in risk for ciated with alcohol dependence, Opioid System. Endogenous opioids drug dependence. For example, a recent GABRA1 (Dick et al. 2006b) is asso­ are small molecules naturally pro­ study determining the of ciated with alcohol-related phenotypes duced in the body that have similar multiple genetic variants across the (e.g., history of alcohol-induced effects as the (e.g., gene uncovered evidence of associa­ blackouts and age at first drunken­ and ) and which, among other tion with OPRM1 and AOD depen­ ness), and GABRG2 (Loh et al. 2007) functions, modulate the actions of dence (Zhang et al. 2006). is associated with aspects of drug other neurotransmitters. The endoge­ Researchers also have investigated dependence. These findings await nous opioid system has been implicated genetic variations in other opioid confirmation in independent samples. in contributing to the reinforcing receptors and other components of effects of several drugs of abuse, includ­ the endogenous opioid system; how­ Genes Involved in the ing alcohol, opiates, and cocaine. ever, the results have been mixed. System. The cholinergic system includes This is supported by the finding that One study (Zhang et al. 2007) found neurons that either release the neuro­ the medication , which modest support that the genes OPRK1 transmitter acetylcholine or respond prevents the normal actions of endoge­ and OPRD1—which encode the κ­ to it. Acetylcholine generally has exci­ nous opioids (i.e., is an opioid antag­ and δ-opioid receptors, respectively— tatory effects in the human central onist), is useful in the treatment of are associated with some aspects of nervous system—that is, it affects alcohol dependence and can reduce drug dependence. Other researchers neurons in a way that enhances their the number of drinking days, amount (Xuei et al. 2007) reported evidence activity. It is thought to be involved of alcohol consumed, and risk of . that the genes PDYN, PENK, and in such processes as , reward, Research on the role of the endoge­ POMC—which encode small molecules learning, and short-term . nous opioids in AOD dependence (i.e., ) that also bind to opi-

Vol. 31, No. 2, 2008 115 oid receptors—may be associated with Conclusions al. 1996). This association remains various aspects of drug dependence. controversial, however, and more recent For both alcohol dependence and studies suggest that the observed asso­ Genes Involved in the Endogenous drug dependence, considerable evi­ ciation actually may not involve vari­ Cannabinoid System. Endogenous dence suggests that genetic factors ants in the DRD2 gene but variants cannabinoids are compounds naturally influence the risk of these disorders, in a neighboring gene called ANKK1 produced in the body that have a with heritability estimates of 50 per­ (Dick et al. 2007b). Studies to identify similar structure to the psychoactive cent and higher. Moreover, twin stud­ candidate genes that influence depen­ compounds found in the ies and studies of electrophysiological dence on illicit drugs, but not on plant and which bind cannabinoid characteristics indicate that the risk of alcohol, are particularly challenging receptors. The endogenous cannabi­ developing AOD dependence, as well because of the high co-morbidity noid system is thought to regulate as other disinhibitory disorders (e.g., between alcohol dependence and brain circuits using the neurotrans­ antisocial behavior), is determined at mitter dopamine, which likely helps least in part by shared genetic factors. dependence on illicit drugs. There­ mediate the rewarding experiences These observations suggest that some fore, meaningful studies require large associated with addictive substances. of a person’s liability for AOD depen­ sample sizes to include enough drug- The main in the dence will result from a general exter­ dependent people with no prior his­ brain is called CB1 and is encoded by nalizing factor and some will result tory of alcohol dependence. the CNR1 gene, which is located on from genetic factors that are more The increasingly rapid pace of chromosome 6. This gene is an excel­ disorder specific. genetic discovery also has resulted in lent candidate gene for being associ­ Several genes have been identified the identification of several genes ated with AOD dependence because that confer risk to AOD dependence. encoding other types of proteins that the receptor encoded by this gene is Some of these genes—such as GABRA2 appear to be associated with alcohol crucial for generating the rewarding and CHRM2— apparently act through use and/or dependence. These include, effects of the compound responsible a general externalizing . for example, two genes encoding for the psychoactive effects associated For other genes that appear to confer receptors (i.e., the TAS2R16 gene with cannabis use (i.e., Δ9-tetrahy­ risk of AOD dependence—such as [Hinrichs et al. 2006] and the drocannabinol). However, the findings genes involved in alcohol metabolism TAS2R38 gene [Wang et al. 2007]) regarding the association between and in the endogenous opioid and and a human gene labeled ZNF699 CNR1 and AOD dependence to date cannabinoid systems—however, the (Riley et al. 2006) that is related to a have been equivocal, with some stud­ pathways through which they affect gene previously identified in the fruit ies producing positive results (e.g., risk remain to be elucidated. Most of Zhang et al. 2004) and others pro­ fly Drosophila as contributing to the the genes reviewed in this article orig­ development of tolerance to alcohol ducing negative results (e.g., Herman inally were found to be associated in the flies. Future research will be et al. 2006). Most recently, Hopfer with alcohol dependence and only necessary to elucidate the pathways and colleagues (2006) found that a subsequently was their association with SNP in the CNR1 gene was associated risk for dependence on other illicit drugs by which these genes influence alco­ with cannabis dependence symptoms. 6 discovered as well. Furthermore, studies hol dependence and/or whether they Moreover, this SNP was part of sever­ that primarily aim to identify genes are more broadly involved in other al sets of multiple alleles that are involved in dependence on certain types forms of drug dependence. ■ transmitted jointly (i.e., ), of drugs may identify different variants some of which are associated with affecting risk, underscoring the chal­ developing fewer dependence symp­ lenge of understanding genetic sus­ Acknowledgments toms, whereas others are associated ceptibility to different classes of drugs. with an increased risk for cannabis This review does not exhaustively Danielle M. Dick is supported by dependence. Finally, a recent cover all genes that to date have been NIAAA grant AA–15416 and Arpana case–control study found that multi­ implicated in alcohol and illicit drug Agrawal is supported by National ple genetic variants in CNR1 were sig­ dependence. For example, several Institute on Drug Abuse (NIDA) grant nificantly associated with alcohol genes encoding receptors for the neuro­ DA–023668. The COGA project is dependence and/or drug dependence transmitter dopamine have been supported by grant U10–AA–08401 (Zuo et al. 2007). suggested to determine at least in part from NIAAA and NIDA. a person’s susceptibility to various forms of drug dependence. In partic­ 6 Financial Disclosure The SNP was not located in one of those gene regions ular, the DRD2 gene has been associ­ that encode the actual receptor (i.e., in an exon) but in a ated with alcohol dependence (Blum region that is part of the gene but is eliminated during the process of converting the genetic information into a pro­ et al. 1990) and, more broadly, with The authors declare that they have no tein product (i.e., in an intron). various forms of (Blum et competing financial interests.

116 Alcohol Research & Health

Genetics of AOD Dependence

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