Novel insights into the common heritable liability to addiction: a multivariate genome-wide association study

Abstract

Addiction to nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability. To elucidate its genetic architecture, we modelled the common liability to addiction, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to addiction, of which 67% were novel and not associated with the six phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine D2 gene), and showed enrichment for several components of the central nervous systems (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviours (e.g., risk-taking, cocaine and heroin use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of addiction, and help to elucidate the common genetic architecture underlying addiction.

Genetic and shared environmental factors explain the association between adolescent polysubstance use and high school noncompletion.

“…While some evidence points to substance-specific causal effects on early school dropout (Grant et al, 2012; Rose et al, 2014; Waldron et al, 2018), our findings on the effects of polysubstance use are consistent with previous studies that suggest much of the risk for adverse outcomes may be driven by factors shared across substances. For example, there is strong evidence that shared genetic factors partially account for the overlap between various substance use behaviors and disorders (Hatoum et al, 2022; Palmer et al, 2012; Schoeler et al, 2021; Sun et al, 2021), and a genetic addiction factor is strongly associated with educational attainment (Schoeler et al, 2021), as well as executive functioning and neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (Hatoum et al, 2022). Furthermore, within a large nationally representative sample, the association between substance use disorders and unemployment, income, and financial problems 3 years later was better explained by a latent addiction factor than by substance-specific effects (Franco et al, 2019).…”