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Genetics of substance use disorders in the era of big data

Nature Reviews Genetics volume 22, pages 712–729 (2021)Cite this article

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Abstract

Substance use disorders (SUDs) are conditions in which the use of legal or illegal substances, such as nicotine, alcohol or opioids, results in clinical and functional impairment. SUDs and, more generally, substance use are genetically complex traits that are enormously costly on an individual and societal basis. The past few years have seen remarkable progress in our understanding of the genetics, and therefore the biology, of substance use and abuse. Various studies — including of well-defined phenotypes in deeply phenotyped samples, as well as broadly defined phenotypes in meta-analysis and biobank samples — have revealed multiple risk loci for these common traits. A key emerging insight from this work establishes a biological and genetic distinction between quantity and/or frequency measures of substance use (which may involve low levels of use without dependence), versus symptoms related to physical dependence.

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Fig. 1: From epidemiology and gene discovery to biology of SUDs.
Fig. 2: Genetic correlation among SUD traits and other phenotypes.
Fig. 3: Twin-based versus SNP-based heritabilities of alcohol, cannabis, cocaine, opioid and tobacco addictions.

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Acknowledgements

The authors are supported by grants from the National Institutes of Health (NIH) (R01DA012690, R01AA026364, U01MH109532, P50AA012870, R01DA037974, R21DA047527 and R21DC018098) and the Department of Veterans Affairs (1I01CX001849). The authors thank D. Levey, Y. Nunez, C. Tyrrell and F. Wendt for their helpful comments.

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  1. Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA

    Joel Gelernter & Renato Polimanti

  2. Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA

    Joel Gelernter & Renato Polimanti

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The authors contributed equally to all aspects of the article.

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Correspondence to Joel Gelernter.

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J.G. and R.P. are paid for their editorial work for Complex Psychiatry journal. J.G. is named as an inventor on PCT patent application #15/878,640 entitled ‘Genotype-guided dosing of opioid agonists’, filed 24 January 2018.

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Glossary

Addictive substances

Psychoactive substances affecting mental processes and causing brain changes associated with the development of physiological dependence.

Substance use

The use of drugs or alcohol, including extrinsic substances such as cigarettes, cannabis, illegal drugs, prescription drugs, inhalants and solvents.

Substance use disorders

(SUDs). According to the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) definition, this diagnostic category combines substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe.

Substance dependence

Mental illness characterized by behavioural, cognitive and physiological symptoms developed after repeated substance use that make it difficult to discontinue use, often despite harmful effects. These symptoms, which extend beyond purely psychological effects, are commonly known as physiological dependence or physical dependence.

Substance abuse

The harmful or hazardous use of psychoactive substances, including alcohol and licit and illicit drugs.

Candidate genes

Loci hypothesized to be associated with a complex traits on the basis of prevailing theories and positional mapping from linkage studies and/or cytogenetic studies.

Diagnostic criteria

Criteria reflecting signs, symptoms and tests that are useful to guide the care of patients and understand prognosis.

Pharmacogenomic

The study of how genomic variation affects individual responses to drugs and drug metabolism.

Epigenetic clock algorithms

Age predictors based on DNA methylation.

Addiction

Exhibiting a psychiatric condition manifested by compulsive substance use despite its harmful consequences.

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Gelernter, J., Polimanti, R. Genetics of substance use disorders in the era of big data. Nat Rev Genet 22, 712–729 (2021). https://doi.org/10.1038/s41576-021-00377-1

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