{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:03:38Z","timestamp":1789632218118,"version":"build-2803163510"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Recent advances in pharmacogenomic guidelines, regulatory labelling, and clinical implementation are supporting broader adoption of pharmacogenetic testing. We analysed whole-genome sequencing data from 3,205 participants in the Medical Genome Reference Bank, a healthy older Australian reference cohort predominantly of European ancestry, to characterise established and novel pharmacogenetic variation. Overall, 1,303 participants (40.7%) carried at least one confirmed homozygous ClinPGx\/PharmGKB Level 1A high-risk configuration. A further 399 participants (12.4%) carried at least one potential-trans, phase-unresolved configuration. After accounting for overlap, 1,566 participants (48.9%) had either a confirmed homozygous or potential-trans, phase-unresolved configuration, representing an upper-bound estimate of potential biallelic involvement rather than confirmed biallelic prevalence. Confirmed homozygous configurations occurred in two or more high-risk pharmacogenes in 255 participants (8.0%) and in three or more genes in 22 participants (0.7%); the corresponding upper-bound estimates were 377 (11.8%) and 45 (1.4%), respectively. None of 409 candidate potential-trans participant\u2013gene configurations could be directly resolved as cis or trans from available phase information. A total of 140 novel predicted loss-of-function participant\u2013gene category records were identified across the high-risk pharmacogene set. Within\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    , 277 participants (8.6%) carried confirmed homozygous Level 1A configurations, although these rsID-defined findings do not represent a complete estimate of\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    metaboliser-phenotype prevalence. Exploratory structural modelling of selected\n                    <jats:italic>OPRM1<\/jats:italic>\n                    missense variants identified variation in predicted fentanyl docking scores and receptor\u2013ligand contact geometry, although these findings require experimental validation. These results demonstrate the value of population-scale whole-genome sequencing for pharmacogenomic discovery while highlighting the importance of distinguishing confirmed homozygous findings from phase-unresolved multi-variant configurations.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1881869","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T07:17:18Z","timestamp":1789629438000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Population prevalence of high-risk pharmacogenetic configurations in a healthy older Australian reference cohort"],"prefix":"10.3389","volume":"17","author":[{"given":"Kosar","family":"Hooshmand","sequence":"first","affiliation":[{"name":"Centre for Molecular Oncology, School of Biomedical Sciences, The University of New South Wales","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Hughes","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie L.","family":"Stocker","sequence":"additional","affiliation":[{"name":"Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney","place":["Sydney, NSW, Australia"]},{"name":"Faculty of Medicine, St. Vincent\u2019s Clinical Campus, University of New South Wales","place":["Sydney, NSW, Australia"]},{"name":"Department of Clinical Pharmacology and Toxicology, St. Vincent\u2019s Hospital","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Somogyi","sequence":"additional","affiliation":[{"name":"Discipline of Pharmacology, College of Health, Adelaide University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy L.","family":"Ballinger","sequence":"additional","affiliation":[{"name":"Centre for Molecular Oncology, School of Biomedical Sciences, The University of New South Wales","place":["Sydney, NSW, Australia"]},{"name":"Omico, the Australian Genomic Cancer Medicine Centre","place":["Kensington, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Centre for Molecular Oncology, School of Biomedical Sciences, The University of New South Wales","place":["Sydney, NSW, Australia"]},{"name":"Omico, the Australian Genomic Cancer Medicine Centre","place":["Kensington, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"595219","DOI":"10.3389\/fphar.2020.595219","article-title":"Pharmacogenetics guidelines: overview and comparison of the DPWG, CPIC, CPNDS, and RNPGx guidelines","volume":"11","author":"Abdullah-Koolmees","year":"2021","journal-title":"Front. 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