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

      Abstract

      Background

      Consumption of nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability to substance involvement.

      Methods

      To elucidate its genetic architecture, we modelled a common liability, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis.

      Results

      Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to substance involvement, 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 opioid use) and mood (e.g., depression, insomnia).

      Conclusions

      These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of substance involvement, and help to elucidate the genetic architecture underlying the use of common psychoactive substances.

      Key words

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