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We sought to identify novel loci for substance use traits (SUTs) in both African\u2010 (AFR) and European\u2010 (EUR) ancestry individuals to enhance our understanding of the traits\u2019 genetic architecture.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>We used multi\u2010trait analysis of GWAS (MTAG) to analyze four SUTs in EUR subjects (OUD, CUD, AUD and smoking initiation [SMKinitiation]), and three SUTs in AFR subjects (OUD, AUD and smoking trajectory [SMKtrajectory]). We conducted gene\u2010set and protein\u2013protein interaction analyses and calculated polygenic risk scores (PRS) in two independent samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>This study was conducted in the United States.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>A total of 5692 EUR and 4918 AFR individuals in the Yale\u2010Penn sample and 29\u2009054 EUR and 10\u2009265 AFR individuals in the Penn Medicine BioBank sample.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>MTAG identified genome\u2010wide significant (GWS) single nucleotide polymorphisms (SNPs) for all four traits in EUR: 41 SNPs in 36 loci for OUD; 74 SNPs in 60 loci for CUD; 63 SNPs in 52 loci for AUD; and 183 SNPs in 144 loci for SMKinitiation. MTAG also identified GWS SNPs in AFR: 2 SNPs in 2 loci for OUD; 3 SNPs in 3 loci for AUD; and 1 SNP in 1 locus for SMKtrajectory. In the Yale\u2010Penn sample, the MTAG\u2010derived PRS consistently yielded more significant associations with both the corresponding substance use disorder diagnosis and multiple related phenotypes than the GWAS\u2010derived PRS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Multi\u2010trait analysis of genome\u2010wide association studies boosted the number of loci found for substance use traits, identifying genes not previously linked to any substance, and increased the power of polygenic risk scores. Multi\u2010trait analysis of genome\u2010wide association studies can be used to identify novel associations for substance use, especially those for which the samples are smaller than those for historically legal substances.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.16229","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T03:11:06Z","timestamp":1683601866000},"page":"1942-1952","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Identifying genetic loci and phenomic associations of substance use traits: A multi\u2010trait analysis of GWAS (MTAG) study"],"prefix":"10.1111","volume":"118","author":[{"given":"Heng","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania 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