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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Review Series

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 2

Illustration of common SNP effect sizes that contribute to underlying latent factor of genetic risk.

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Illustration of common SNP effect sizes that contribute to underlying la...
Simulated effects of 100 independent SNPs predicting four simulated SUD traits are plotted as a heatmap. A genetic correlation of 0.70 is assumed between all traits, consistent with genetic correlations between SUDs. When a SNP effect is more similar across all four traits, that SNP will have a larger contribution to the latent underlying genetic predisposition. A single row is circled to demonstrate such consistency across the effect sizes of a SNP on the four traits. As the risk allele for the SNP in the circled row has a similar magnitude of negative effect on all four traits, that SNP is likely contributing to the inheritance of each trait and is likely a “common” effect. Many rows follow a similar consistent pattern of effect sizes, while others do not. This highlights that a genetic correlation of 0.70 includes both SNPs that capture consistent, or shared, effects, but also SNPs that may have specific effects on each trait.