Generalized genetic liability to substance use disorders
Alex P. Miller, … , Arpana Agrawal, Alexander S. Hatoum
Alex P. Miller, … , Arpana Agrawal, Alexander S. Hatoum
Published June 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e172881. https://doi.org/10.1172/JCI172881.
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Generalized genetic liability to substance use disorders

Abstract

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Authors

Alex P. Miller, Ryan Bogdan, Arpana Agrawal, Alexander S. Hatoum

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Figure 1

Early evidence for a generalized genetic liability to SUDs (SUD-g) arose from genetic epidemiological studies examining the coaggregation of various SUDs in related individuals.

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Early evidence for a generalized genetic liability to SUDs (SUD-g) arose...
(A) Family studies found that relatives of a proband (dark purple; i.e., an index individual with a SUD) were at heightened risk for multiple SUDs. The degree of coaggregation varied by the degree of genetic relatedness; i.e., first-degree relatives such as siblings were most likely to have other SUDs. (B) Within twin pairs, including genetically identical monozygotic twins, there was evidence for cross-substance genetic correlations (e.g., one twin’s alcohol use disorder was associated with the other twin’s alcohol, tobacco, and opioid use disorders). (C) These family studies and across-SUD twin correlations led to the identification of a latent genetic factor underlying these SUDs.