Aetiology

Genetics of addictionDavid Ball

Abstractthe observation that addiction can run in families, and that this is in part

determined by genetic factors, has been confirmed by family, twin and

adoption studies. the actual genes that underpin this genetic contribu-

tion to vulnerability are being sought and identified using a combination

of approaches including genetic linkage and association. Ultimately, the

identification of the complex interaction between genes and environ-

ment that occurs during the process of addiction development will pro-

vide the framework through which potential treatment approaches can

be developed and targeted.

Keywords addiction; dependence; genes; genetics

Four main theoretical approaches to the aetiology of addiction have held sway over the years: • availability and acceptability of substance use/behaviour • personality • self-medication • hereditary factors. This contribution examines the latter, although it should be stressed that these theories are not mutually exclusive and overlap; for example, there are genetic contributions to personality and psychi-atric disorders that may lead to substance use and addiction. Start-ing with the evidence from family studies that genes are involved in the predisposition to addiction there follows a critical review of the molecular genetic attempts to dissect that involvement.

Genes and environment

The phrase ‘nature–nurture’ implies a dichotomy between genetic and environmental factors that simply does not exist in reality. Rather like an intricate dance, addiction is the result of a complex interaction between genetic and environmental factors that occurs during a process of development. During this pro-cess different genes and environmental factors are important at different stages of the disease process.

David Ball PhD MRCPsych is Senior Lecturer and Honorary Consultant

Psychiatrist at the Social, Genetic and Developmental Psychiatry Centre

at the Institute of Psychiatry and the South London and Maudsley

NHS Trust, London, UK. He qualified from the University of Oxford and

trained as a psychiatrist on the Bristol rotation. He joined the Institute

of Psychiatry in 1992. His research attempts to unravel the genetic

contributions to alcohol dependence. Conflicts of interest: none

declared.

PSyCHiAtRy 5:12 44

Currently, the genetic and environmental exploration of alco-hol dependence is more advanced than that of drug dependence. In part this is due to the wide availability and acceptability of alcohol in many societies; as such, the high rate of misuse changes slowly over long periods of time. Consequently there is a relatively high prevalence of alcohol dependence, with many of those affected seeking treatment, and it is possible to recruit families and individuals for genetic studies. As regards illicit drugs, future opportunities for research will increase as their use becomes more prevalent.

Family studies

Evidence that genes are involved in the predisposition to addic-tion is derived from family, twin and adoption studies. The clus-tering of addiction in families is consistent with, but not proof of, a genetic contribution. Further evidence for a genetic role can be provided by adoption studies and an estimate of the herit-ability (crudely speaking, how genetic the condition is) from twin studies.

Alcohol use: alcohol dependence clusters in families, and the rates in adopted-away individuals with a biological parent with alcohol dependence are increased when compared with adopted individuals who do not have such a parent. Indeed one study indicated that being adopted away from an alcohol-dependent father confers no protective effect.1 Twin studies of alcohol dependence yield typical estimates of heritability of 0.5 for males and 0.25 for females.2

Drug use: two major population-based twin studies in the USA have examined the role of genes in substance misuse. The Vietnam Era Twin (VET) registry yielded heritabilities of between 0.25 and 0.44 for abuse and/or dependence for the various substances studied, including cannabis, opiates, stimu-lants, sedatives, phencyclidine (PCP) and psychedelics.3 In the Virginia twin studies, heritabilities were approximately double those found in the VET study.4,5 In this latter study estimates for women were close to those for men.

Smoking: the genetic contribution to smoking has been sub-divided into initiation and maintenance, with typical heritabili-ties of 0.4 for the former and 0.5 for the latter.6

Molecular genetic approaches

Initial attempts to identify the genes contributing to addiction employed genetic association approaches. These studies compare the distribution of a genetic marker (a piece of DNA that differs between individuals and can be identified) in unrelated affected individuals and in controls. Association studies are effective in identifying genes of relatively small effect, and have typically been used to study candidate genes that are implicated by virtue of their putative function. To apply this approach systematically, for a complete genome scan, would require the use of many thousands of markers: this is now becoming possible using ‘DNA chips’ that can examine 1,000,000 markers at a time.7 Linkage studies examine the inheritance of genetic markers in families, attempt-ing to identify a co-inheritance of a marker and addiction. This

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Aetiology

systematic approach can be completed using just 300 markers, but it is effective at identifying genes of relatively large effect only.

Results from linkage studiesAlcohol: two linkage studies have identified candidate regions in alcohol dependence. One study minimized confounding fac-tors by recruiting families from a southwestern American Indian tribe (thus ensuring ethnic homogeneity). The best evidence for linkage was found between a marker on chromosome 11 and alcohol dependence. There was also good evidence for linkage at a region on chromosome 4.8 The results of the larger Collab-orative Study on the Genetics of Alcoholism (COGA) provided evidence of linkage on chromosomes 1 and 7, with a protective locus on chromosome 4 near the alcohol dehydrogenase (ADH) gene cluster.9

Smoking: three linkage studies of smoking behaviour have been reported, with inconsistent results implicating loci on chromo-somes 2, 4, 5, 6, 9, 10, 14, 16, 17 and 18.10

Results from association studiesAlcohol: while association studies have implicated many genes in the predisposition to addiction, the only consistently repli-cated findings are those genes involved in alcohol metabolism and alcohol dependence in Asian populations.

The major pathway for ethanol metabolism occurs in the liver. The first step is catalysed by alcohol dehydrogenase (ADH), which is actually a group of enzymes. Genetic variants occur in two of these enzymes (ADH2 and ADH3), and the slow variants have been associated with alcohol dependence (see Figure 1). In addition, perhaps the most robust finding in psychiatric genetics has been the protection afforded by the inactive variant of alde-hyde dehydrogenase (ALDH2) – the second step in this metabolic pathway – against the development of alcohol dependence (see Figure 2). This variant is produced by a single nucleotide differ-ence in the gene, which results in an amino acid change such that the protein is inactive. As a result, following ingestion of alcohol, an individual with this genetic variant experiences the ‘oriental flush’ reaction – marked facial flushing, amongst other symp-toms, due to acetaldehyde accumulation. Disulfiram (Antabuse), which is used to help maintain abstinence in alcohol-dependent individuals, inhibits this enzyme.

Other genes implicated in alcohol dependence by associa-tion studies11 include genes of the γ-aminobutyric acid (GABA), opiate, dopamine and serotonin (5-HT) systems.2

Drugs: in opiate addiction, genes of the dopamine, opiate, cannabinoid and serotonin systems have been implicated.12,13

Smoking: in smoking, possible associated genes have been described in the dopamine, serotonin, nicotine and nicotine metabolism systems.10,14

Conclusion

Family, twin and adoption studies provide strong evidence for a substantial genetic contribution to addiction. It is highly likely that this genetic vulnerability will consist of two components, the first a general predisposition to addictive behaviour and the

PSyCHiAtRy 5:12 44

First step in alcohol metabolism

First step in the primary metabolic pathway for ethanol showing

genetic variants of the three class I enzymes.

Alcohol Acetaldehyde

Alcohol dehydrogenase

(ADH)

ADH2 ADH3ADH1

ADH22ADH1 ADH2

1 ADH23 ADH3

1 ADH32

Figure 1

Second step in alcohol metabolism

Second step in the primary metabolic pathway for ethanol

showing genetic variations of aldehyde dehydrogenase 2 (ALDH2),

which is also the site of action of disulfiram (Antabuse), a

medication used to aid the maintenance of abstinence.

AcetateAcetaldehyde

Aldehyde dehydrogenase 2

Disulfiram (Antabuse)

ALDH22ALDH2

1

Figure 2

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Aetiology

second a specific vulnerability to use of a particular substance. Two main approaches have been adopted to identify individual genes, namely linkage and association. Linkage has highlighted specific chromosomal regions; association studies have suggested specific genes implicated in the predisposition to, and protection from, addiction. Identifying the genes will help explain the bio-logical underpinnings of addiction. This will provide a logical framework for the development and targeting of drugs that could have a dramatic effect on the (currently poor) treatment out-comes in this field. Furthermore, identification of the biological factors will, in turn, help elucidate those environmental factors that are of importance. ◆

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