{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:55:46Z","timestamp":1790949346658,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA013736"],"award-info":[{"award-number":["AA013736"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA023192"],"award-info":[{"award-number":["AA023192"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA028292"],"award-info":[{"award-number":["AA028292"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA030056"],"award-info":[{"award-number":["AA030056"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA03510"],"award-info":[{"award-number":["AA03510"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alcohol, Clinical and Experimental Research"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In two 12\u2010week, randomized, placebo\u2010controlled trials (RCTs) in individuals with alcohol use disorder (AUD), topiramate significantly reduced heavy drinking days (HDDs), and alcohol\u2010related problems. In a secondary analysis of those findings, we examined four broad measures of genetic risk\u2014polygenic scores (PGS)\u2014of problematic alcohol use (PAU), drinks per week (DPW), and time to relapse to any drinking (TR) and heavy drinking (THR) as moderators of topiramate's effect on HDDs and alcohol\u2010related problems.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed data from 285 individuals with AUD (65.6% male) of European\u2010like ancestry, who were treated with either topiramate (49.1%) or placebo (50.9%). All patients underwent genome\u2010wide array genotyping, and PGS were calculated using summary statistics from genome\u2010wide association studies of PAU, DPW, and TR and THR (two time\u2010to\u2010event outcomes among patients treated in AUD pharmacotherapy trials). We hypothesized an interaction effect in which greater genetic risk\u2014particularly for PAU\u2014would be associated with a greater therapeutic response to topiramate than placebo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      As shown previously, topiramate significantly reduced both HDDs (odds ratio [OR]\u2009=\u20090.50,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and Short Index of Problems (SIP) scores (\n                      <jats:italic>b<\/jats:italic>\n                      \u2009=\u2009\u22123.04,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) more than placebo. There were nonsignificant associations of higher PGS with more HDDs (OR\u2009=\u20091.17, 95% CI\u2009=\u20090.98\u20131.41,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.091) and a greater reduction in HDDs in the topiramate group (OR\u2009=\u20090.80, 95% CI\u2009=\u20090.62\u20131.03,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.089). There were also significant interaction effects with treatment on SIP score by PGS for PAU (\n                      <jats:italic>b<\/jats:italic>\n                      \u2009=\u2009\u22121.64, SE\u2009=\u20090.78,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.033), TR (\n                      <jats:italic>b<\/jats:italic>\n                      \u2009=\u2009\u22122.16, SE\u2009=\u20090.72,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003), and TRH (\n                      <jats:italic>b<\/jats:italic>\n                      \u2009=\u2009\u22122.17, SE\u2009=\u20090.72,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings provide proof of principle for the use of alcohol\u2010related PGS as moderators of the effects of topiramate for treating AUD. Larger RCTs of topiramate are needed to provide adequate statistical power to validate this pharmacogenetic approach to precision AUD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/acer.70052","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T11:00:43Z","timestamp":1748602843000},"page":"1297-1305","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Moderation of treatment outcomes by polygenic risk for alcohol\u2010related traits in placebo\u2010controlled trials of topiramate"],"prefix":"10.1111","volume":"49","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 Pennsylvania USA"},{"name":"Mental Illness Research, Education and Clinical Center Crescenz VAMC  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeal","family":"Jinwala","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Mental Illness Research, Education and Clinical Center Crescenz VAMC  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3974-5598","authenticated-orcid":false,"given":"Christal N.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Mental Illness Research, Education and Clinical Center Crescenz VAMC  Philadelphia Pennsylvania 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 Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna M.","family":"Biernacka","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Psychiatry and Psychology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Yale University School of Medicine and VA CT Healthcare Center  West Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8820-2659","authenticated-orcid":false,"given":"Rachel L.","family":"Kember","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Mental Illness Research, Education and Clinical Center Crescenz VAMC  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Gelernter","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Yale University School of Medicine and VA CT Healthcare Center  West Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Feinn","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Frank H. 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