Review Paper

Genetics and Alcoholism: How Close Are We to Potential Clinical Applications?

Jeremy Quickfall, MD¹, Nady el-Guebaly, MD, FRCPC²

Despite the explosion of genetic knowledge in substance use disorders and psychiatry in general, there are few clinical applications of this information. Nevertheless, it is conceivable to envision future clinical practice that uses existent knowledge and technology. Genetics in psychiatry carries the promise of use in various facets of practice. Screening, diagnosis, prognosis, and treatment are all areas wherein genetic data are applied routinely in some areas of medicine. We present major methodologies used in genetic research and principal findings (which demonstrate a heritable component to alcoholism), followed by a discussion of intermediate phenotypes or endophenotypes—characteristics thought to have more consistent genetic underpinnings. We also discuss genetic influences in the potential pharmacologic management of alcoholism.

Review of the Literature

The body of literature discussing the genetics of alcoholism is vast and steadily increasing. A search of the PubMed database up to December 1, 2005, yielded 4491 articles; of these, 1931 were published in the last 10 years. Therefore, this article does not purport to be an exhaustive review of the subject or a critique of the varied and complex methodologies used throughout this field. We paid particular attention to general review articles dealing with the genetics of alcoholism (see 1–7) and to articles where a potential clinical application was relevant. Selected areas, which we deemed of interest, were investigated in greater depth and are presented below; we acknowledge that many more such areas likely exist than those discussed here.

Evidence for a Heritable Component in the Development of Alcoholism

Twin and Adoption Studies

Twin and adoption studies examine shared genetic material while controlling for environmental influences. Most of the very large twin or adoption studies published in the last 10 years support a significant genetic contribution to the development of alcoholism (3,8–12) and estimate that, based on these studies, 50% to 60% of alcoholism’s etiologic factors are genetic in origin (2,3,11). Further, this level of genetic liability is roughly equal in men and women, although, as Heath and colleagues point out, “women with the same degree of genetic risk [as men] are less likely to become alcoholics” (9, p 1392); They suggest there may be more of an interplay between genes and environment in women to reach a risk threshold high enough to develop alcoholism. This is supported by adoption studies that hypothesize that, in women, family conflict and psychopathology interact with genes to lead to alcoholism (13).

There is also evidence to support strong heritability factors in each of the principle diagnostic systems used in alcohol research. Using a multiple threshold model of alcoholism diagnosis (that is, a narrow definition implying alcoholism with physiological dependence, compared with broader definitions that are less inclusive), Kendler and others demonstrated highly concordant rates of heritability among female twins, regardless of the criteria used (8). Despite differing estimates of heritability among 3 diagnostic systems (the DSM-III, Cloninger Type I–II, and Feighner I–II; 14–16), each shows a strong genetic contribution to alcoholism risk (17).

A smaller twin study of 133 pairs showed that certain diagnostic interviewing criteria showed significantly higher genetic loading (18) for particular questions using the DIS-III. Questions relating to job or school trouble, health problems secondary to alcohol, binges and “eye-openers,” and a period of sustained drinking longer than 2 weeks were all under significant genetic influences. In addition, there was an inverse association between genetic subscale scores and age of first alcohol problems, as well as for the interval between age of first intoxication to age of onset of alcohol problems.

The twin and adoption studies from which current estimates of heritability are derived are large, well-designed, and rigorously controlled. However, there are limitations. Most of these studies were done in populations of Northern European background and may not be applicable to those of other ethnicities (3). In addition, many of the study designs relied on questionnaires to assess alcohol use histories, which are often subject to bias. However, the replicability of the findings and their consistency suggests that they are reliable, at least in the context in which they are presented.

Linkage Studies

Linkage studies involve the comparison of affected and nonaffected individuals within families or other large groups (for example, alcoholics and nonalcoholics) to look for the presence of chromosomal markers that occur with a higher than random distribution (19). Linkage studies can identify regions of interest on particular chromosomes but do not identify the gene in which the marker lies. Two large and widely cited linkage studies have been published in the last several years. One is a large, multicentre, American study wherein identified probands were recruited along with their families. A total of 987 individuals comprising 105 families were genotyped and screened for polymorphic markers throughout their genome. Significant linkages for the risk of alcoholism were found on chromosomes 1 and 7, with a more modest linkage on chromosome 2 (20). Interestingly, a marker for a protective gene was identified on chromosome 4, near the ADH locus, which has been shown to confer some degree of resistance to alcoholism in Asian populations. The COGA sample contains few Asian families, however, and it has been theorized that another protective gene, or a yet undiscovered allele of an ADH gene, may also be present at this site (21). A replication study published in 2000 (22) of 1295 individuals in 157 families supported the original findings of markers on chromosomes 1 and 7 and strengthened the evidence for involvement of genes on chromosome 2. A new marker with significant linkage was also identified on chromosome 3.

A major limitation of the COGA sample is that, even though the families enrolled were of primarily European descent, there was a considerable amount of genetic heterogeneity. This is a potential confounder in the search for multiple genes or genetic markers each having a small additive contribution to the development of a disorder such as alcoholism. A second study by the National Institute on Alcohol Abuse and Alcoholism involved a linkage study of a Southwest American Indian tribe with a much more genetically and environmentally homogeneous population (23), which thus controlled for many of these extraneous variables. Two markers showed significant linkages that were near genes with known neurophysiologic relevance to the biology of alcohol use. One marker on chromosome 11 was in close proximity to the D4 dopamine receptor and tyrosine hydroxylase genes, whereas another marker on chromosome 4 was near the beta 1 GABA receptor gene.

Linkage studies require no prior knowledge of the genes at the identified sites on chromosomes or their putative function. However, these are often known through prior chromosomal mapping and sequencing studies, which can lead to further work testing the role of the gene in the pathogenesis of alcoholism. Linkage studies can be used not only to identify risk for a particular illness but also to identify genomic areas of interest for other traits and markers associated with that disease. Currently, in the COGA sample, linkage analyses are underway to identify markers related to psychiatric comorbidity, endophenotypes related to alcoholism, and specific characteristics of alcohol-dependent individuals who may be under greater genetic influence (24–27).

Candidate Genes

Molecular approaches to identifying genes or chromosomal regions of interest generally fall into 2 types: linkage studies and association studies (5). Association studies are case– control studies in which a group of affected individuals are compared with matched control subjects to look for the presence of a particular allele. In this type of study, the candidate gene is already suspected for its contribution to the etiology of the condition. This method has been criticized for systemic limitations in study design, and thus newer and more refined methods of association studies have been developed and used more commonly (28,29). Over the last decade, there has been considerable interest in identifying specific genes that are implicated in the pathophysiology of alcoholism, which has been reviewed extensively elsewhere (2,7). Although it is unlikely that there is a single alcoholism gene, multiple genes (which may exist in various allelic distributions in individuals) each exert a small effect to reach a threshold of liability when combined with environmental factors. Genes are associated both with risk and protection and are linked to the heritability of comorbid medical and psychiatric illness—specific traits seen in people with alcoholism and their offspring—and patterns or symptoms of alcohol abuse or dependence. Most genes implicated are related to neurotransmission or alcohol metabolism. We discuss some of these below.

Intermediate Phenotypes and the Risk of Alcoholism

A further dimension to identifying the genetic factors in alcoholism is the concept of the intermediate phenotype, or endophenotype. This is defined as a “measurable component[s] unseen by the unaided eye along the pathway between disease and distal genotype” (30, p 636). Often, this trait is detected by laboratory means not readily observable and can therefore be more rigorously studied with quantitative methods. It has been suggested that at least 3 characteristics, or intermediate phenotypes, that modulate the risk of developing alcoholism have a significant heritable component (31). The level of response to alcohol’s intoxicating effects; variations in alcohol metabolism, that is, the enzymes primarily responsible for alcohol breakdown; and impulsivity are endophenotypes thought to be highly involved in the pathway to the development of alcoholism.

Level of Response

LR refers to the intoxicating effects of alcohol that are independent from an individual’s blood ethanol level (and thus metabolism) or rate of excretion. Individuals with low LR, then, experience fewer subjective and objective signs of intoxication for a given amount of alcohol, compared with the general population. It has been estimated that genes contribute between 40% and 60% to the etiology of LR (32,33). A low LR is thought to predispose an individual to alcoholism by decreasing the given “reward” for a specific amount of alcohol. The individual may thus progressively consume more to achieve a state of intoxication in a cycle of physiological tolerance and the need to further increase the amount consumed. In an 8-year follow-up study of 453 sons of subjects with alcoholism and sons of control subjects, lower LR at age 20 years predicted future alcoholism (and no other psychiatric comorbidity) regardless of drinking pattern at the same age (34). Mounting evidence shows similar trends in daughters of people with alcoholism (35). Several chromosomal regions have been identified in the COGA study as having linkages to low LR (36). Genes related to the GABA-A receptor subunits as well as the serotonin transporter have been implicated (37).

Alcohol Metabolism

Perhaps the most compelling evidence for a genetic role associated with alcoholism risk or protectiveness is that of genes regulating alcohol metabolism. The genes of 2 of these enzymes make significant contributions to the heritability of alcoholism. The first, ADH, converts alcohol to acetaldehyde. The final enzymatic step is the conversion of acetaldehyde to acetic acid through ALDH. It is this intermediate compound that is responsible for the characteristic “flushing” response, which includes facial flushing, feelings of warmth, increased heart rate and respiratory rate, nausea, and headache (47).

The ADH enzyme comprises 3 subunits, each one the product of different genes: ADH1, ADH2, and ADH3, of which ADH2 and ADH3 have polymorphic forms (4). Asian populations, which have significantly different allelic distributions, compared with Europeans, have been studied extensively. To what extent the findings apply to non-Asian populations, however, remains unclear (4), although data suggest similar trends in populations of Jewish ancestry as well (48–50). ADH2 and ADH3 have polymorphic alleles (ADH2q1, 2·2, and 2·3, and ADH3·1 and 3·2), although ADH2 is the only isozyme with significant independent effects on alcoholism risk (51,52). ADH2·2 converts alcohol to acetaldehyde at a much faster rate than ADH2·1 and is thought to confer protection when individuals are homozygous for this allele. ADH2·1 has been found to be positively associated with alcoholism in populations of Japanese men and Han Chinese men. It is estimated that Japanese men homozygous for the 1·1 allele are 4 times more likely to have alcohol dependence than are those who are heterozygous and are 6 to 7 times more likely than are those homozygous for the 2·2 allele (4,51,52). A metaanalysis exploring the relation between ADH genotype and alcoholism concluded that the 2·1 allele is associated with an almost threefold increase in risk to develop alcoholism, compared with the 2·2 allele. However, the same study also found that the 2·2 allele increases the risk for alcoholic liver disease when present in alcohol dependent individuals (53).

ALDH enzymes are encoded by a large family of genes, of which ALDH2 is the most physiologically relevant for the breakdown of acetaldehyde to acetic acid (which is then excreted from the body). This enzyme is found in 2 polymorphic forms, ALDH2q1 and ALDH2q2, the latter having almost no activity (4). Deficient breakdown of acetaldehyde causes a flushing response in heterozygotes and an extremely aversive picture of toxicity in homozygous individuals (similar to the flushing response caused by the hyperactive ADH allele, as noted). This low-efficiency allele is essentially absent in those of Northern European descent and is far more prevalent in Asian populations, with an estimated 43% of the Japanese population having at least one copy (54). The effect of being homozygous for the 2q2 allele has such a strong effect that no occurrences of this genotype were identified in several large series of Asian subjects with alcoholism (55–57). Both hetero- and homozygous individuals have an increased aversive reaction when also homozygous for the ADH2q2 gene, demonstrating a further interaction between the 2 gene products (58).

Whereas being homozygous for the ADH 2q2 gene has shown to be protective, there can be increased risk of serious illness in those who have this genetic trait yet nevertheless abuse alcohol. A metaanalysis concluded that people with alcoholism who are homozygous for ADH2q2 have a significantly increased risk of alcoholic liver disease (53). Other studies have shown an association between having a single copy of the ALDH2q2 allele and higher rates of alcohol-related cancers (such as oropharyngeal, stomach, colon, and lung cancer) (59,60).

Impulsivity

CD and ASPD are 2 similar disorders characterized by persistent and remorseless behaviours in violation of societal norms that are destructive, deceitful, or aggressive, both to self and others (38). CD is an antecedent to ASPD, and both have a very high comorbidity to substance use disorders. Several twin studies have shown a shared genetic link between CD and ASPD and alcoholism (39,40), and another demonstrated a shared heritability between the personality dimension of “behavioral undercontrol” characterized by impulsivity, aggressiveness, thrill-seeking, rebelliousness, and alcohol dependence. The authors hypothesize that a genetic liability to these personality traits predisposes an individual to the development of both alcoholism and CD and (or) ASPD (41). This is similar to type II alcoholism, described by Cloninger, which is characterized by early onset, antisocial traits, and a positive family history of alcohol dependence. Using the COGA study linkage, there is evidence suggesting a shared genetic basis for alcoholism and suicide (42). It is then possible to hypothesize that the underlying trait leading to these phenotypes is impulsivity. Several studies have implicated the SS allele of the serotonin transporter in individuals with alcoholism with violent or suicidal behaviour (43–46); these individuals are consistent with those with type II alcoholism who have a positive family history, early-onset drinking, and dissocial or impulsive behaviours.

Pharmacogenetics in the Treatment of Alcohol Dependence

Pharmacogenetics can be defined as the study of interindividual pharmacodynamic and pharmacokinetic differences of substances secondary to interindividual differences in genotypes (61). Increased understanding of the genetics of drug response, metabolism, and genetic differences associated with various conditions has allowed this area to become highly clinically relevant in other areas of medicine. It has been suggested that pharmacogenetic techniques may one day play a role in psychiatry through optimizing drug selection (such as in depression) as well as through identifying those at risk for various side effects, such as tardive dyskinesia in schizophrenia patients (61). Although there are no current clinical indications for pharmacogenetic interventions in the assessment and treatment of alcoholism, current research suggests that, like other areas of psychiatry, it may one day form part of the framework from which clinicians choose a treatment approach.

Craving and anxiety were found to be significantly reduced by bromocriptine, a dopamine agonist, in subjects meeting DSM-III-R criteria for alcohol dependence who carried the TaqA1 allele of the dopamine D2 receptor gene (62). In a completer analysis, those who were positive (either homo- or heterozygous) for this allele had lower scores in craving and anxiety, compared with subjects who did not carry any copies or those given placebo. In a study of the mu-opioid receptor, subjects with 1 of 2 alleles of the coding gene, OPRM1, were identified from 3 previous trials using naltrexone to reduce craving in those with alcohol dependence (63). Two studies were placebo-controlled, double-blinded trials, while the third trial included a third arm of subjects randomly assigned to nefazodone. A total of 260 subjects received naltrexone and 206 received placebo. Those with the Asn40 allele were significantly less likely to relapse (defined by a return to heavy drinking, that is, 5 or more drinks in a single day for men and 4 or more for women) when on naltrexone than subjects without this allele, and subjects with the allele who were given placebo.

While not an efficacy trial, a recent report demonstrated a reduction in the subjective effects of alcohol in a subset of 27 healthy social drinkers using finasteride, a 5-alpha reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (64). Subjects with the GABRA2(A) allele reported significantly greater effects of alcohol than did those with the (G) allele, which is associated with dependence, but had attenuated responses after finasteride administration prior to drinking.

The role of the serotonergic system has been the subject of much scrutiny and debate with regard to both the pathogenesis and treatment of alcohol dependence. Early reports of success with SSRIs in the treatment of alcoholism (65) were tempered by later studies that did not support this presumed efficacy, and several authors proposed that, in fact, only a subset of those with alcohol use disorders were amenable to treatment with serotonergic medications (66–68). Two subpopulations were delineated: those with early-onset alcoholism, characterized by young age of drinking onset, a familial history of alcohol use problems, and antisocial personality traits; and those with late-onset alcoholism, generally characterized by onset of alcohol dependence after age 25 years and a childhood history of no CD (15,66,69).

The 5-HT transporter is a membrane-bound protein responsible for reuptake of 5-HT from the synaptic cleft; it is the principle site of action of SSRIs. The coding gene for this protein, 5HTTLPR, has 2 alleles, the LL, whose gene product has greater reuptake activity, and the SS allele. Johnson and colleagues have hypothesized that the 5-HT abnormalities underlying this problem lie with polymorphisms of the 5-HT transporter (70). Increased uptake (and subsequent lowered levels of intrasynaptic 5-HT) would lead to upregulation of 5-HT₃ receptors and tonically attenuated dopaminergic activity. Intoxication would lead to reinforcement of reward pathways. Blocking 5-HT₃ receptors would lead to a decrease in dopamine release; thus, the rewarding properties of intoxication would be lessened. Ondansetron, a 5-HT₃ receptor antagonist, has been shown to decrease craving in biologically predisposed (early-onset) individuals with alcoholism while increasing cravings in those with late-onset alcoholism (71, 72). Those with late-onset alcoholism, with either the SL or SS phenotype, are therefore hypothesized to have normal transporter activity and intrasynaptic 5-HT levels; SSRIs would produce a modest increase that is known to tonically downregulate dopamine release, thus decreasing reward. Indeed, in this group, SSRIs have been shown to reduce craving and increase abstinence, while in some reports, have increased craving in those with early-onset alcoholism (67).

Future Directions

While clinical applications of genetic knowledge are presently limited in the field of psychiatry, rapid advancement allows speculation on facets of the management of alcoholism that may one day make use of this information. Screening in both clinical and nonclinical populations can identify those at risk for alcohol use disorders (73–75). Screening for such characteristics as level of response, impulsivity, and alcohol metabolism may allow for earlier identification of individuals at risk, leading to preventative measures or early intervention. Inquiries such as family history are standard parts of medical interviewing and constitute a “quasi-heritability” line of investigation (76,77); modification or addition of further probes may strengthen the ability to detect individuals at highest risk for falling prey to alcohol use disorders, from a genetic point of view.

The field of pharmacogenetics seems closest in many ways to providing clinical applicability in the treatment of alcoholism. Neurobiological research that implicates gene products of dopaminergic and opioid neurotransmitter systems has shown that the presence or absence of various alleles improves efficacy in reducing craving and lengthening time to relapse in preliminary studies. Subtypes of alcoholism have been theorized on the basis of allelic differences in serotonergic function, which may inform treatment decisions and aid in appropriate selection of pharmacotherapies. Larger studies in treatment settings are needed to evaluate the use of these interventions; endeavors such as the Combining Medications and Behavioral Interventions study (78) aim to examine a multiplicity of factors in the treatment of alcoholism and include pharmacogenetic studies on treatment response to the anticraving medications naltrexone and acamprosate (79). Clearly, as our basic and clinical knowledge of the underlying mechanisms of the genetics of alcoholism progresses, our optimism for real-world solutions to this widespread problem can grow as well.

Funding and Support

Partial support was provided by the Alberta Alcohol and Drug Abuse Commission.

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Author(s)

Manuscript received June 2005, revised, and accepted Fanuary 2006.

1. Psychiatry Resident, Department of Psychiatry, University of Calgary, Calgary, Alberta.

2. Professor, Department of Psychiatry, University of Calgary, Calgary, Alberta; Medical Director, Foothills Addiction Centre, Calgary, Alberta.

Address for correspondence: Dr J Quickfall, Department of Psychiatry, Foothills Medical Centre, 1403 29th St. NW, Calgary AB T2N 2T9

e-mail: Jeremy.Quickfall@CalgaryHealthRegion.ca

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