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The Genetics of Alcohol and Other Drug Dependence

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The Genetics of Alcohol and Other Drug Dependence The Genetics of Alcohol and Other Drug Dependence Danielle M. Dick, Ph.D., and Arpana Agrawal, Ph.D. Alcohol dependence and dependence on other drugs 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 psychopathology 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 genes as affecting risk for dependence on alcohol and other drugs. These include genes involved in alcohol metabolism as well as in the transmission of nerve cell signals and modulation of nerve cell activity (i.e., γ-aminobutyric acid [GABA] and acetylcholinergic neurotransmission and the endogenous opioid and cannabinoid 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 Epidemiology 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 Alcohol dependence frequently co- assess the extent to which the co­ alcohol abuse 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 psychiatry, psychology, conduct disorder. After summarizing 1999). Dependence on illicit drugs and human 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 brain 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, schizophrenia (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 humans. 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 & Health 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 human genome 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
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