across brain and nerve tissues (Extended Data Fig. 3a and Supplementary Table 5). Within the brain, cell-type enrichment of the high-priority genes was observed for projecting glutamatergic neurons from the cortex, hippocampus and amygdala (telencephalon excitatory projection neurons) and projection GABA neurons from medium spiny neurons of the striatum (telencephalon inhibitory projecting neurons), along with neurons in various subcortical structures such as the hypothalamus and midbrain, consistent with aspects of the mesolimbic theory of addiction7,8 (Extended Data Fig. 3b). Finally, these high-priority genes that were strongly associated with substance use were enriched in gene pathways related to neurogenesis, neuronal development, neuronal differentiation and synaptic function. The neurodevelopmental aspect of the high-priority genes could indicate a role for these genes in processes that predispose individuals to risk of substance use and/or may contribute to brain circuit rewiring during drug use.
