Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders

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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.

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