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We investigated the genetic architecture underlying the lifetime use (LU) of several drugs, individually and in combination.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S0033291725101293_sec2\" sec-type=\"methods\">\n\t    <jats:title>Methods<\/jats:title>\n\t    <jats:p>We conducted genome-wide association studies of LU of cocaine, methamphetamine, inhalants, illegal opioids, prescription opioids, and prescription stimulants in European (EUR), African (AFR), and Latin American (AMR)-ancestry subjects (cases ranging from <jats:italic>n<\/jats:italic>\u00a0=\u00a04,900\u201321,850 [EUR], <jats:italic>n<\/jats:italic>\u00a0=\u00a0519\u20139,802 [AFR], and <jats:italic>n<\/jats:italic>\u00a0=\u00a0899\u20135,012 [AMR]; controls from <jats:italic>n<\/jats:italic>\u00a0=\u00a093,763\u2013110,658 [EUR], <jats:italic>n<\/jats:italic>\u00a0=\u00a037,261\u201346,509 [AFR], and <jats:italic>n<\/jats:italic>\u00a0=\u00a031,412\u201335,501 [AMR]). We also investigated the use of illicit drugs of any kind and the total count of drugs a person has ever used. Then, we assessed the global and local genetic correlations between substance LU (SubLU) traits and their genetic correlations with other traits.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S0033291725101293_sec3\" sec-type=\"results\">\n\t    <jats:title>Results<\/jats:title>\n\t    <jats:p>We found numerous genes that affect SubLU traits, with no overlap among the significant loci between traits, suggesting that unique genetic factors may differentially affect the use of different drugs. Nevertheless, the genetic correlations between SubLU traits were very strong; however, the phenotypic correlations were moderate. There were strong genetic correlations between various SubLU traits and psychiatric traits, most notably opioid use disorder, cannabis use disorder, problematic alcohol use, and suicidality.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S0033291725101293_sec4\" sec-type=\"conclusions\">\n\t    <jats:title>Conclusions<\/jats:title>\n\t    <jats:p>Our findings provide insights into the genetic basis of substance use, identifying several novel genes associated with SubLU traits. This study can provide an improved understanding of the biology underlying SubLU and could potentially facilitate future risk assessments for the use of illicit and hazardous drugs.<\/jats:p>\n\t  <\/jats:sec>","DOI":"10.1017\/s0033291725101293","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:43:22Z","timestamp":1753875802000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":5,"title":["Differences and similarities between the genetic architecture of lifetime substance use across different substances"],"prefix":"10.1017","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9102-7804","authenticated-orcid":false,"given":"Uri","family":"Bright","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassie","family":"Overstreet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel 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