Genomic insights into substance use and disinhibitory disorders

Externalizing spectrum disorders-spanning attention-deficit/hyperactivity disorder, conduct disorder, substance use disorders, and other disorders characterized by disinhibition-frequently co-occur within individuals due, in part, to shared genetic etiology. To advance understanding of this genetic architecture, we conducted a multi-ancestry, multivariate genome-wide association analysis of more than 4 million individuals, identifying 1,294 genomic regions linked to an externalizing factor. Fine-mapping and gene prioritization efforts identified 961 effector genes, with the putative causal variant associations showing robust replication in the All of Us Research Program sample. Bioinformatic analyses revealed a broadly distributed neural architecture with early and sustained involvement of GABAergic and glutamatergic neurons. Drug repurposing analyses further highlighted the role of GABA_A receptors, as well as dopaminergic signaling, excitatory-inhibitory balance, and neurosteroid pathways. A genome-wide polygenic index predicted ~12% of the variance in externalizing in independent cohorts of individuals with European-like ancestry, compared to ~3% in individuals with African-like ancestry, and was associated with myriad health and life outcomes. Together, these findings map the shared genetic etiology of externalizing psychopathology and identify neurodevelopmental and synaptic mechanisms with translational relevance.