{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:15:03Z","timestamp":1784679303391,"version":"3.55.0"},"reference-count":53,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA054071"],"award-info":[{"award-number":["DA054071"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DP1DA054394"],"award-info":[{"award-number":["DP1DA054394"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["1R01DA061977\u201001"],"award-info":[{"award-number":["1R01DA061977\u201001"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1 TR000445\u201006"],"award-info":[{"award-number":["UL1 TR000445\u201006"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["R01MH137220"],"award-info":[{"award-number":["R01MH137220"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["1R01MH118233"],"award-info":[{"award-number":["1R01MH118233"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction Biology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome\u2010wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure (\u2018generic\u2019) versus minimally opioid\u2010exposed control (\u2018exposed\u2019). First, at the phenotypic level, we conducted phenome\u2010wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD\u2010related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16\u2009\u00b1\u20090.07 vs. 0.10\u2009\u00b1\u20090.07), associations with the coding\n                    <jats:italic>OPRM1<\/jats:italic>\n                    variant rs1799971 (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>generic<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20098.83E\u201003 vs.\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>exposed<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20091.83E\u201002) and genetic correlations with prior OUD GWAS (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>g\u2010generic<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.83\u2009\u00b1\u20090.26 vs.\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>g\u2010exposed<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.78\u2009\u00b1\u20090.27). Although GWASs were limited by sample size (\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sub>generic<\/jats:sub>\n                    \u2009=\u20096269,\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sub>exposed<\/jats:sub>\n                    \u2009=\u20096365), compared to an independent OUD GWAS (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009425\u2009944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.\n                  <\/jats:p>","DOI":"10.1111\/adb.70094","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T08:21:01Z","timestamp":1768810861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimizing Control Definitions in Opioid Use Disorder Genetic Research Using Electronic Health Records"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8855-7393","authenticated-orcid":false,"given":"Maria","family":"Niarchou","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Genetic Medicine Vanderbilt University  Nashville Tennessee 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kritika","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Genetic Medicine Vanderbilt University  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6671-6816","authenticated-orcid":false,"given":"Justin\u00a0D.","family":"Tubbs","sequence":"additional","affiliation":[{"name":"Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Center for Precision Psychiatry, Department of Psychiatry Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Department of 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Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon\u00a0J.","family":"Coombes","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5729-632X","authenticated-orcid":false,"given":"Georgios","family":"Voloudakis","sequence":"additional","affiliation":[{"name":"Department of Genetic and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Center for Disease Neurogenomics Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Friedman Brain Institute Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Center for Precision Medicine and Translational Therapeutics JJ Peters VA Medical Center  Bronx New 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USA"},{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"},{"name":"Institute for Genomic Medicine University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"National Institute on Drug Abuse (NIDA).Drug Overdose Deaths: Facts and Figures [Internet].2024[cited 2025 Aug 26]. Available from:https:\/\/nida.nih.gov\/research\u2010topics\/trends\u2010statistics\/overdose\u2010death\u2010rates."},{"key":"e_1_2_11_3_1","unstructured":"S.Curtin Trends in Death Rates for Leading Methods of Injury: United States [Internet] 2025. Available from:https:\/\/www.cdc.gov\/nchs\/products\/databriefs\/db526.htm#:~:text=The%20rate%20declined%206%25%20from by%20drug%20overdoses%20in%202013."},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2014.366"},{"key":"e_1_2_11_5_1","unstructured":"Centers for Disease Control and Prevention.Provisional Drug Overdose Death Counts 2024 [Internet]. Available from:https:\/\/www.cdc.gov\/nchs\/nvss\/vsrr\/drug\u2010overdose\u2010data.htm."},{"key":"e_1_2_11_6_1","volume-title":"Disorder, GMOU. NCBI Bookshelf","author":"Dydyk A. M."},{"key":"e_1_2_11_7_1","unstructured":"United States Congress Joint Economic Committee.The Economic Toll of the Opioid Crisis Reached Nearly $1.5 Trillion in 2020 [Internet].2022[cited 2025 Aug 26]. Available from:https:\/\/www.jec.senate.gov\/public\/index.cfm\/democrats\/2022\/9\/the\u2010economic\u2010toll\u2010of\u2010the\u2010opioid\u2010crisis\u2010reached\u2010nearly\u20101\u20105\u2010trillion\u2010in\u20102020."},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40429-025-00672-5"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291723003732"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI172886"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00377-1"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0183-z"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0609-7"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2019.01.007"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000525079"},{"issue":"1","key":"e_1_2_11_16_1","article-title":"Identifying Problematic Opioid Use in Electronic Health Record Data: Are We Looking in the Right Place?","volume":"19","author":"Schirle L.","year":"2023","journal-title":"Journal of Opioid Management"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12148"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2012.01450.x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2010.05.020"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmedinf.2021.104621"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01160-z"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01709-1"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22588"},{"key":"e_1_2_11_24_1","unstructured":"L.Wang Y. 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