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The estimated heritability of SUDs is ~50% and many individuals experience multiple SUDs concurrently. Studies have demonstrated the existence of genes shared across multiple SUDs, and identifying these SUD-shared genes is critical to developing novel prevention and treatment strategies. Here, we conducted the largest cross SUD meta-analysis to date to identify SUD-shared genes using samples genetically similar to 1000 Genomes Project European (1kg-EUR-like), African (1kg-AFR-like), and American mixed (1kg-AMR-like) populations. We defined variants that had the same direction of effects across different SUDs (i.e., concordant variants) as SUD-shared. In total, we identified 220 loci, including 40 novel loci that were not reported as SUD-associated in previous genome-wide association studies. Through gene-based analyses, gene mapping, and gene prioritization, we identified 785 SUD-shared genes. These genes are highly expressed in the amygdala, cortex, hippocampus, hypothalamus, and thalamus; and are primarily highly expressed in neuronal cells, suggesting that more brain regions may be involved in SUDs than previously reported. Concordant variants explained 56\u201396% of the SNP-heritability of each SUD in the 1kg-EUR-like sample. Furthermore, the top 10% of individuals in the 1kg-EUR-like and 1kg-AMR-like samples with the highest polygenic scores had odds ratios ranging from 1.95\u20132.87 to develop SUDs, and these polygenic scores could potentially be used to identify high-risk individuals. Lastly, using a real-world dataset, we identified seven SUD-shared genes targeting drugs that may be repurposed for treating SUDs, particularly in those suffering from comorbid SUDs.<\/jats:p>","DOI":"10.1038\/s41380-025-03294-5","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T13:10:41Z","timestamp":1759842641000},"page":"1619-1633","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genome-wide meta-analyses of cross substance use disorders in diverse populations"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7803-580X","authenticated-orcid":false,"given":"Dongbing","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1457-879X","authenticated-orcid":false,"given":"Nick","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Abreu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6387-0095","authenticated-orcid":false,"given":"Tae-Hwi","family":"Schwantes-An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa C.","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0025-4337","authenticated-orcid":false,"given":"Fulai","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0344-9690","authenticated-orcid":false,"given":"Howard J.","family":"Edenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2699-626X","authenticated-orcid":false,"given":"Yunlong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5549-2212","authenticated-orcid":false,"given":"Tatiana","family":"Foroud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"3294_CR1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/S2215-0366(18)30337-7","volume":"5","author":"L Degenhardt","year":"2018","unstructured":"Degenhardt L, Charlson F, Ferrari A, Santomauro D, Erskine H, Mantilla-Herrara A, et al. 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