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<sub>A</sub> 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.

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Publication Details

Journal
medRxiv
Published
2026-02-09
DOI
https://doi.org/10.64898/2026.02.09.26344198
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

Genomic insights into substance use and disinhibitory disorders

Mariela Jennings, Justin D. Tubbs, Diego Londoño-Correa, Marijn Schipper et al.
medRxiv
Genetic Associations and Epidemiology
article

Genomic insights into substance use and disinhibitory disorders

Mariela Jennings, Justin D. Tubbs, Diego Londoño-Correa, Marijn Schipper, Abraham A. Palmer, R. deVlaming, Matthew Rosenblatt, Emily Balcke, Sarah J. Brislin, Tammi R. A. Kral, Peter T. Tanksley, Richard Karlsson Linnér, Nathaniel Y. Bell, Joseph D. Deak, Tanya N. Phung, Javier de la Fuente, Fazil Aliev, Danielle Dick, EM Johnson, Maia Choi, Yuchen Ning, Holly Poore, Peter B. Barr, Sandra Sanchez-Roige, Irwin D. Waldman, Michael J. Gandal, Elliot M. Tucker-Drob, Natasia S. Courchesne-Krak, Hang Zhou, Kai Yuan, Jean Gonzalez, Travis Triplett Mallard, Danielle Posthuma, Jordan W. Smoller, Joel Gelernter, Tian Ge, COGA Collaborators
article en

Abstract

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<sub>A</sub> 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.

medRxiv
Rutgers, The State University of New Jersey (US), Broad Institute (US), Leiden University (NL), Centre National de la Recherche Scientifique (FR), State University of New York (US), Children's Hospital of Philadelphia (US), Texas State University (US), Harvard University (US), Emory University (US), SUNY Downstate Health Sciences University (US), Washington University in St. Louis (US), Université Paris Sciences et Lettres (FR), VA NY Harbor Healthcare System (US), Johnson University (US), Amsterdam UMC Location University of Amsterdam (NL), École Normale Supérieure - PSL (FR), Yale University (US), University of California San Diego (US), VA Connecticut Healthcare System (US), Massachusetts General Hospital (US), Amsterdam Neuroscience (NL), Environmental and Occupational Health Sciences Institute (US), Laboratoire de Sciences Cognitives et Psycholinguistique (FR), Center for Genomic Science (IT), The University of Texas at Austin (US), Vrije Universiteit Amsterdam (NL), Vanderbilt University Medical Center (US), École des hautes études en sciences sociales (FR)
Georgia Clinical and Translational Science Alliance, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 57%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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