Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (N cases =33,977, N controls =675,392) in four broad ancestry groups: European (EUR) (N cases =22,564, N controls =624,672), African (AFR) (N cases =7,574, N controls =34,189), Admixed American (AMR) (N cases =3,657, N controls =15,698), and East Asian (EAS) (N cases =182, N controls =833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2 *rs5794864, P =7.32×10 −10 , one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5 *rs55781567, P =3.27×10 −9 , two in a male-only meta-analysis, including FTO *rs8057044, P =9.50×10 −9 , and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (N EUR =18,841, N AFR =12,263, N AMR =9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1 , BSN ). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (r g =0.94, P =5.43×10 −237 ) and opioid use disorder (r g =1.01, P =4.40×10 −107 ), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.
Source: medRxiv
Authors: Sarah E. Beck, Joseph D. Deak, Daniel F. Levey, Tian Ge, Paul W. Jeffries, Dongbing Lai, Travis T. Mallard, Louisa Degenhardt, Penelope A. Lind, Trine Tollerup Nielsen, Justin D. Tubbs, Leah Wetherill, Emma C. Johnson, Alexander S. Hatoum, COGA Collaborators, The VA Million Veteran Program, Anders D. Børglum, Ditte Demontis, Sarah E. Medland, Nicholas G. Martin, Elliot C. Nelson, Jordan W. Smoller, Henry R. Kranzler, J. Michael Gaziano, Murray B. Stein, Arpana Agrawal, Howard J. Edenberg, Joel Gelernter
Institutions: Yale University, VA Connecticut Healthcare System, Broad Institute, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Washington University in St. Louis, Indiana University Indianapolis, Indiana University School of Medicine, UNSW Sydney, National Drug and Alcohol Research Centre, Queensland University of Technology, The University of Queensland, QIMR Berghofer Medical Research Institute, Aarhus University, Lundbeck Foundation, Massachusetts Institute of Technology, Philadelphia VA Medical Center, University of Pennsylvania, Brigham and Women's Hospital, VA Boston Healthcare System, University of California San Diego, VA San Diego Healthcare System
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G2905247291, G3809296745, Risk and Resilience in Developmental Diversity and Mental Health, G4772171027, Adding value to Medicare/PBS to find the genetic causes of mental health problems and translate this to preventive measures, Tackling heterogeneity in the etiology of major depressive disorder, G6436024939, Using genomics and imaging to advance our understanding of mental health challenges, Improving Knowledge and Interventions to reduce and prevent substance use related harms, 2/7 Psychiatric Genomics Consortium: Advancing Discovery and Impact, Leveraging record linkage for single-indication medications to boost recruitment in Psychiatric and Pharmaco- Genetics
OpenAlex ID: W7164352190
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