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We measured the impact of genetic risk for substance use disorders (SUDs) on substance use onset and progression of symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, Setting, Participants<\/jats:title>\n                    <jats:p>Using findings from genome\u2010wide association studies (GWASs) of alcohol use disorder (AUD), opioid use disorder (OUD) and smoking trajectory (SMK) as discovery samples, we calculated polygenic risk scores (PRSs) in a deeply phenotyped independent target sample. Participants in the target sample were recruited from 2000 to 2020 from US inpatient or outpatient settings or through advertisements and comprised 5692 European\u2010ancestry individuals (EUR) (56.2% male) and 4918 African\u2010ancestry individuals (AFR) (54.9% male).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements<\/jats:title>\n                    <jats:p>This study measured age of first substance use, regular use, reported problems and dependence diagnosis and progression from regular use to onset of problems and dependence for alcohol, opioids and smoking. We examined the contribution of PRS to each milestone and progression measure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      EUR and males reported an earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol\u2010related milestones (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001). Although\u00a0the AUD PRS was a stronger moderator of problem onset among females (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.017), it was more predictive of the progression to problems among males (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.005). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001). Among AFR, where power is lower due to the smaller discovery sample, AUD PRS predicted age of regular alcohol use (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.039) and dependence (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.001) and progression from regular use to diagnosis (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.045), while SMK PRS predicted earlier age of initiation (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.036).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Genetic risk for SUDs appears to predict substance use milestones and symptom progression among European\u2010ancestry individuals and, to a lesser extent, African\u2010ancestry individuals.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/add.16210","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T23:44:48Z","timestamp":1681775088000},"page":"1675-1686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Does polygenic risk for substance\u2010related traits predict ages of onset and progression of symptoms?"],"prefix":"10.1111","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-0450","authenticated-orcid":false,"given":"Henry R.","family":"Kranzler","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"},{"name":"Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4 Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Feinn","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Frank H. Netter School of Medicine at Quinnipiac University  North Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0870-3822","authenticated-orcid":false,"given":"Brendan L.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Saini","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia R.","family":"Nicastro","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya","family":"Jacoby","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvanus","family":"Toikumo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"},{"name":"Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4 Crescenz Veterans Affairs Medical Center  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Gelernter","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Yale University School of Medicine  New Haven CT USA"},{"name":"VA Connecticut Healthcare System  West Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5137-9714","authenticated-orcid":false,"given":"Emily E.","family":"Hartwell","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia PA USA"},{"name":"Department of Medical Sciences Frank H. 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