{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T14:38:09Z","timestamp":1754145489894,"version":"3.41.2"},"reference-count":26,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01 BX003341"],"award-info":[{"award-number":["I01 BX003341"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016284","name":"VISN 4 Mental Illness Research, Education, and Clinical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016284","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><jats:sec><jats:title>Background<\/jats:title><jats:p>Topiramate reduces alcohol consumption in individuals who drink heavily. Candidate gene studies aimed at identifying genetic variants that predict topiramate's effects on drinking have yielded inconsistent findings. To identify genetic variation associated with treatment response, we conducted a genome\u2010wide association study (GWAS) among participants in the Million Veteran Program (MVP) who initiated topiramate treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using electronic health records, we identified individuals who were dispensed topiramate for at least 60\u2009days for any indication (i.e., the index event). Alcohol consumption was assessed using Alcohol Use Disorders Identification Test\u2010Consumption (AUDIT\u2010C) scores during the year prior to topiramate exposure (pre index) and at least 60\u2009days after initiating topiramate but within 6\u2009months of drug discontinuation (post index). The final GWAS sample included 8386 individuals who reported alcohol consumption (i.e., AUDIT\u2010C score\u2009&gt;\u20090) during the preceding year. We calculated polygenic scores (PGS) for topiramate treatment response in the Yale\u2010Penn sample (<jats:italic>n<\/jats:italic>\u2009=\u200910,275) and examined associations with 692 phenotypes using a phenome\u2010wide association study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the cross\u2010ancestry GWAS meta\u2010analysis, 35 loci had suggestive associations, though none reached genome\u2010wide significance. Topiramate response PGS had nominally significant associations with lower rates of alcohol\u2010related liver disease, older age at alcohol use disorder diagnosis, and higher frequency of alcohol use.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Although no loci reached genome\u2010wide significance, the suggestive variants identified in the cross\u2010ancestry meta\u2010analysis are promising candidates for future investigation. Larger studies are needed to identify significant genetic predictors of topiramate response and advance precision medicine strategies for treating AUD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.70069","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T06:29:20Z","timestamp":1746426560000},"page":"1197-1205","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010ancestry genome\u2010wide association study of topiramate's effects on heavy alcohol use"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3974-5598","authenticated-orcid":false,"given":"Christal N.","family":"Davis","sequence":"first","affiliation":[{"name":"Mental Illness Research, Education and Clinical Center Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"},{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeal","family":"Jinwala","sequence":"additional","affiliation":[{"name":"Mental Illness Research, Education and Clinical Center Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"},{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-5502","authenticated-orcid":false,"given":"Amy C.","family":"Justice","sequence":"additional","affiliation":[{"name":"Veterans Affairs Connecticut Healthcare System  West Haven Connecticut USA"},{"name":"Department of Internal Medicine Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher T.","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yale School of Medicine  New Haven Connecticut USA"},{"name":"Faculty of Epidemiology and Population Health London School of Hygiene &amp; Tropical Medicine  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-0450","authenticated-orcid":false,"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[{"name":"Mental Illness Research, Education and Clinical Center Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"},{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsat.2008.05.007"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01097-0"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/acer.12411"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.158.16.1789"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13742\u2010015\u20100047\u20108"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13225-y"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/02698811221149643"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ps.201000553"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.03.004"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2022.08.010"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2013.13081014"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.15980"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-020-00945-9"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs\u20102021\u20100108"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08494"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.19761"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.20230666"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e32833d7b45"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05477-4"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1010"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","unstructured":"Verma A. Huffman J.E. Rodriguez A. Conery M. Liu M. Ho Y.L.et\u00a0al. (2023)Diversity and scale: genetic architecture of 2 068 traits in the VA million veteran program.medRxiv. Available from:https:\/\/doi.org\/10.1101\/2023.06.28.23291975","DOI":"10.1101\/2023.06.28.23291975"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"}],"container-title":["Alcohol, Clinical and Experimental Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acer.70069","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T02:22:17Z","timestamp":1752718937000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acer.70069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,5]]},"references-count":26,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1111\/acer.70069"],"URL":"https:\/\/doi.org\/10.1111\/acer.70069","archive":["Portico"],"relation":{},"ISSN":["2993-7175","2993-7175"],"issn-type":[{"type":"print","value":"2993-7175"},{"type":"electronic","value":"2993-7175"}],"subject":[],"published":{"date-parts":[[2025,5,5]]},"assertion":[{"value":"2025-01-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}