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  • Review Article
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The genetics of addictions: uncovering the genes

Nature Reviews Genetics volume 6, pages 521–532 (2005)Cite this article

Key Points

  • Addictions are common chronic psychiatric diseases that are characterized by persistent, compulsive and uncontrolled use.

  • Addictions are a worldwide public-health issue, causing 12.4% of deaths.

  • Addictions are among the most heritable psychiatric diseases; heritabilities range from 0.39 (hallucinogens) to 0.72 (cocaine).

  • Monozygotic:dizygotic twin concordance ratios for addictions are approximately 2:1, indicating that interactions among multiple genes (polygenicity) might not be required for vulnerability.

  • Animal studies model addiction-relevant behaviours and have led to an understanding of addiction neurobiology and the identification of several genes that mediate variation in drug preference and response.

  • The neurobiological pathways that modulate reward, stress resiliency and behaviour inhibition are among those that also underlie general addiction liability.

  • Across the addictions, the correlation of addiction liability with heritability indicates that variation in the core neurobiology of addiction is genetically influenced.

  • Cross-inheritance studies in twins indicate that both substance-specific and substance-nonspecific genetic factors are important in addictions, and that there is cross-inheritance between addictions and other psychiatric disorders. Linkage studies have identified genes that are of both these general types.

  • Treatment and prevention of addictions are partially successful because medical management targets the acute phase of illness and is not individualized.

  • The individualization of treatment and prevention is likely to be advanced by the discovery of genetic predictors of the neurobiological pathways that underlie addiction.

Abstract

The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods. The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioural control and the anxiety or stress response. Our future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors and a role in shared vulnerabilities such as variation in reward or stress resiliency.

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Figure 1: Lifetime prevalence of substance use in 6 countries.
Figure 2: Heritability of addictive disorders.
Figure 3: Genetic complexity in unrelated individuals and its effect on twin concordance.
Figure 4: Weighted means of monozygotic and dizygotic tetrachoric correlation ratios for 10 addictive disorders.
Figure 5: Clusters of the γ-aminobutyric acid (GABA) subunit genes in humans.

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Acknowledgements

We gratefully acknowledge E. Gordis for his helpful comments on this manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, 20852, Maryland, USA

    David Goldman, Gabor Oroszi & Francesca Ducci

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  1. David Goldman
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  2. Gabor Oroszi
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  3. Francesca Ducci
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Correspondence to David Goldman.

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Related links

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DATABASES

Entrez gene

ADH1B

ALDH2

BRCA1

COMT

DRD4

HTR1B

MAOA

Omim

Schizophrenia

Type 1 diabetes

FURTHER INFORMATION

Collaborative Study on the Genetics of Alcoholism

International HapMap Project

National Institute on Drug Abuse Genetic Consortium

National Institute on Drug Abuse report —Addiction burden in the USA

Request proposals for access to a whole genome association scanning resource to identify addiction loci

World Health Organization — Global status report on alcohol, 2004

World Health Organization report — The global burden of addiction

Glossary

AFFECTIVE DISTURBANCE

An abnormal or inappropriate emotion or mood.

POINT PREVALENCE

The proportion of individuals who have a phenotype at a specified point in time or within a defined timeframe (for example, 1 year).

DISABILITY ADJUSTED LIFE YEAR

The years of life that are lost due to premature mortality or disability.

PSYCHOPATHOLOGY

A psychiatric disease, or the manifestation of a psychiatric disease.

POLYGENICITY

A model of genetic determinism in which many alleles function in combination to produce a phenotype.

HETEROGENEITY

A model of genetic determinism in which different alleles lead to the same phenotype in different individuals, but an individual allele can suffice to produce the phenotype.

HERITABILITY

An estimate of the genetic component of liability, which ranges from zero to one.

ADDICTION LIABILITY

The relative potential of an agent to lead to addiction.

ABUSE

Substance abuse is a disease that is operationally defined using objective criteria such as those issued by the American Psychatric Association and the World Health Organization.

RESILIENCY

The ability to withstand mental or physical stress.

OLIGOGENICITY

A model of genetic determinism in which a few alleles function in combination to produce a phenotype.

HAPLOTYPE

A combination of alleles at different loci on the same chromosome.

COMORBIDITY

The co-occurrence of two or more diseases in an individual or an excess of disease co-occurrence in a population.

PHENOCOPY

Describes the situation in which a phenotype of an environmental origin mimics a phenotype of a genetic origin.

GENOCOPY

Describes the situation in which a phenotype of a genetic origin mimics a phenotype of a different genetic origin.

PENETRANCE

The probability of expressing a phenotype that is determined by a genotype.

LOCUS-BASED LINKAGE

The detection of locus-to-locus or locus-to-phenotype genetic linkage. This is generally accomplished by detecting a lack of meiotic recombination in families in which alleles at one locus are observed to be in coupling (co-transmitted) or repulsion (not co-transmitted) with alleles at a second locus.

LINKAGE DISEQUILIBRIUM

The excess and complementary deficit of combinations of alleles at two different loci, which is based on rarity of meiotic recombination between loci on the same chromosome.

BENZODIAZEPINE DRUGS

Structurally similar selective GABAA receptor agonists that have potent anxiolytic, sedative, central muscle relaxant and anti-epileptic properties.

QUANTITATIVE TRAIT LOCUS

A genetic locus that is identified through the statistical analysis of complex traits (such as body weight). These traits are typically affected by more than one gene and by the environment.

PHARMACODYNAMIC

Relating to the response of cells and tissues to drugs.

PHARMACOKINETIC

Relating to drug absorption, distribution or metabolism.

MANIA

A pathological elevated mood-state that is associated with mental and physical hyperactivity.

PANIC DISORDER

An anxiety disorder characterized by paroxysms of overwhelming fear with associated somatic, behavioural and cognitive symptoms.

AGORAPHOBIA

An anxiety disorder that is characterized by fear and avoidance of places from which escape might be difficult.

BULIMIA

An eating disorder that is characterized by recurrent binge eating, which is accompanied by self-induced purging and/or other inappropriate compensatory behaviours.

ALLOSTASIS

A new homeostatic (maintained) equilibrium that lies outside the normal range and is characterized by long-lasting adaptational mechanisms that are activated in response to a stressor.

CATECHOLAMINES

A class of structurally similar amine neurotransmitters, including dopamine, noradrenaline and adrenaline, that are derived from the amino acid tyrosine.

WISCONSIN CARD-SORT TEST

A neurocognitive test of frontal lobe function that requires the subject to switch strategies that are needed to match cards to a target.

N-BACK TEST

A neurocognitive test of frontal lobe function and working memory that requires the recall of an earlier stimulus after a new stimulus (or stimuli) has been presented.

WORKING MEMORY

A memory system that is activated for temporary storage and manipulation of information while a mental task is carried out.

WARRIOR/WORRIER MODEL

A selectionist explanation for the maintenance of COMT alleles that have counterbalancing effects in cognition versus resilience to stress and anxiety.

AMYGDALA

A complex region of the brain temporal lobe that is important in modulating emotional states.

AGONISTS

Molecules that bind to receptors and elicit signal transduction.

ANTAGONISTS

Molecules that bind to receptors and, although they do not have intrinsic action, inhibit signal transduction.

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Goldman, D., Oroszi, G. & Ducci, F. The genetics of addictions: uncovering the genes. Nat Rev Genet 6, 521–532 (2005). https://doi.org/10.1038/nrg1635

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