{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:52:20Z","timestamp":1791402740551,"version":"4.3.3"},"reference-count":19,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"\n \n \n CYP2D6<\/jats:italic>\n is a highly polymorphic pharmacogene responsible for the metabolism of more than 20% of commonly prescribed drugs. Clinical implementation of\n CYP2D6<\/jats:italic>\n pharmacogenetics relies on star allele nomenclature and the Activity Score system, yet substantial interindividual variability in drug exposure remains unexplained. A recent study proposed that the so-called J1 haplotype, defined by rs2267439 C>T located 285\u2009kb downstream of\n CYP2D6<\/jats:italic>\n , improves phenotype prediction when combined with revised activity values for selected alleles. However, accurate resolution of the phase of the J1 variant with star alleles requires long-read sequencing due to the distant genomic location of rs2267439 from the gene. In this study, we used phased long-read sequencing data from 884 pediatric subjects to characterize the distribution of the J1-defining variant across\n CYP2D6<\/jats:italic>\n star alleles. Additionally, we evaluated the functional impact of the variants defining the J1, L, and O1 unphased haplotypes on risperidone metabolism in a Nigerian cohort of 125 patients treated with risperidone using targeted genotyping. Phased long-read sequencing revealed that the J1\/rs2267439 variant is broadly distributed across\n CYP2D6<\/jats:italic>\n star alleles of all functional categories (normal, decreased, and no function) without preferential co-segregation with any specific allele. In the risperidone-treated African unphased cohort, J1, L, and O1-defining variants were highly prevalent, yet none were associated with statistically significant differences in risperidone metabolic ratios across\n CYP2D6*1\/*1<\/jats:italic>\n ,\n *1\/*2<\/jats:italic>\n , or\n *1\/*29<\/jats:italic>\n diplotype groups. These findings suggest that testing the J1, L, and O1-defining variants may not improve\n CYP2D6<\/jats:italic>\n -based phenotype prediction for risperidone. Incorporation of these variants into clinical guidelines requires further validation across diverse populations and multiple substrates.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000623","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:00:10Z","timestamp":1791399610000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Distribution of the J1 haplotype variant rs2267439 across CYP2D6 diplotypes and its impact on risperidone metabolism"],"prefix":"10.1097","author":[{"given":"Antonio","family":"Asensi Canto","sequence":"first","affiliation":[{"name":"Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain"},{"name":"Pharmacy Department, Virgen de la Arrixaca University Hospital, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy Y.","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children\u2019s Mercy Kansas City, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin C.","family":"Boone","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children\u2019s Mercy Kansas City, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Retke","sequence":"additional","affiliation":[{"name":"Mass Spectrometry & Bioanalysis Core, Children\u2019s Mercy Research Institute, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Toren","sequence":"additional","affiliation":[{"name":"Mass Spectrometry & Bioanalysis Core, Children\u2019s Mercy Research Institute, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byunggil","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Mercy Kansas City, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oyinlade","family":"Kehinde","sequence":"additional","affiliation":[{"name":"Child and Adolescent Mental Health Service Center (CAMHSC) Federal Neuro\u2010Psychiatric Hospital, Lagos, Nigeria"},{"name":"Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel E.","family":"Vaughn","sequence":"additional","affiliation":[{"name":"Division of Child & Adolescent Psychiatry, Department of Pediatrics, University of Cincinnati College of Medicine & Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ogochukwu","family":"Amaeze","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy & Biopharmacy, University of Lagos, Lagos, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinyemi","family":"Oni-Orisan","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gaedigk","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children\u2019s Mercy Kansas City, Kansas City, Missouri, USA"},{"name":"Department of Pediatrics, University of Missouri\u2013Kansas City, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura B.","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children\u2019s Mercy Kansas City, Kansas City, Missouri, USA"},{"name":"Department of Pediatrics, University of Missouri\u2013Kansas City, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"R1-20261007","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation.","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol Ther"},{"key":"R2-20261007","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1007\/s40262-019-00750-8","article-title":"Physicochemical properties, biotransformation, and transport pathways of established and newly 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Ther"},{"key":"R11-20261007","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1002\/cpt.70012","article-title":"Cytochrome P450 2D6 *17 and *29 allele activity for risperidone metabolism: advancing precision medicine health equity.","volume":"118","author":"Kehinde","year":"2025","journal-title":"Clin Pharmacol Ther"},{"key":"R12-20261007","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.gim.2022.02.007","article-title":"Genomic answers for children: dynamic analyses of >1000 pediatric rare disease genomes.","volume":"24","author":"Cohen","year":"2022","journal-title":"Genet Med"},{"key":"R13-20261007","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/nbt.4235","article-title":"A universal SNP and small-indel variant caller using deep neural networks.","volume":"36","author":"Poplin","year":"2018","journal-title":"Nat Biotechnol"},{"key":"R14-20261007","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve years of SAMtools and BCFtools.","volume":"10","author":"Danecek","year":"2021","journal-title":"GigaScience"},{"key":"R15-20261007","article-title":"StarPhase: comprehensive phase-aware pharmacogenomic diplotyper for long-read sequencing data.","author":"Holt","year":"2024","journal-title":"bioRxiv"},{"key":"R18-20261007","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1093\/bioinformatics\/btv402","article-title":"LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants.","volume":"31","author":"Machiela","year":"2015","journal-title":"Bioinformatics"},{"key":"R19-20261007","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/btae042","article-title":"HiPhase: jointly phasing small, structural, and tandem repeat variants from HiFi 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