The genetic landscape of substance use disorders

Abstract

Substance use disorders represent a significant public health concern with considerable socioeconomic implications worldwide. Twin and family-based studies have long established a heritable component underlying these disorders. In recent years, genome-wide association studies of large, broadly phenotyped samples have identified regions of the genome that harbour genetic risk variants associated with substance use disorders. These regions have enabled the discovery of putative causal genes and improved our understanding of genetic relationships among substance use disorders and other traits. Furthermore, the integration of these data with clinical information has yielded promising insights into how individuals respond to medications, allowing for the development of personalized treatment approaches based on an individual's genetic profile. This review article provides an overview of recent advances in the genetics of substance use disorders and demonstrates how genetic data may be used to reduce the burden of disease and improve public health outcomes.

Fig. 1. A summary of GWAS findings for major substance use disorders.

a Number of genomic loci associated with substance use disorders verse GWAS sample size (see Supplementary Table 1). b SNP-based heritability (h²snp) and variance explained by polygenic scores (R² PGS) for substance use disorders (extracted from refs. [9, 18, 26, 42, 43]). Notes: AUD alcohol use disorder, CUD cannabis use disorder, OUD opioid use disorder, TUD tobacco use disorder, Effective N effective sample size.

Fig. 2. Pleiotropy between substance use disorders.

a Genetic correlations between substance use disorders (extracted from refs. [25, 26, 138], which estimated correlations using linkage disequilibrium score regression). b Substance use disorders cluster to form a general addiction factor (path coefficients extracted from model reported in Hatoum et al. [10]., estimated using genomic structural equation modelling).

Fig. 3. Genetic overlap between substance use disorders and other complex traits.

Genetic correlations between alcohol use disorder (AUD), cannabis use disorder (CUD), opioid use disorder (OUD), tobacco use disorder (TUD) and a range of complex traits. Genetic correlations extracted from recent studies that applied linkage disequilibrium score regression (refs. [9, 18, 25, 26, 43, 138]). Error bars represent 95% confidence intervals.

Fig. 4. Putative causes and consequences of substance use disorders from Mendelian Randomization studies.

This figure displays traits that have been found to causally influence the risk of major substance use disorders (“Causes”) and traits that are influenced by these disorders (“Consequences”). Negative directions of effect are displayed in green (−) while positive directions of effects are influenced in red (+). Note that this figure includes traits with a reported causal association with substance use disorders but does not consider the strength of evidence of causation or effect size of the association.